Mitochondria as target for antiischemic drugs

Advanced Drug Delivery Reviews 49 (2001) 151–174 www.elsevier.com / locate / drugdeliv

Mitochondria as target for antiischemic drugs Didier Morin a , *, Thierry Hauet b , Michael Spedding c , Jean-Paul Tillement a a

´ de Paris XII, Laboratoire de Pharmacologie and Centre National de La Recherche Scientifique, Faculte´ de Medecine ´ , France 8 rue du General Sarrail, F-94010 Creteil b ´ ` , France , INRA le Magneraud, Surgeres Unite´ de Transplantation Expetimentale c Institut de Recherches Internationales Servier ( IRIS), 192 avenue Charles de Gaulle, 92200 Neuilly sur Seine, France Accepted 5 February 2001

Abstract The cessation of blood flow followed by a reperfusion period results in severe damages to cell structures. This induces a complex cascade of events involving, more particularly, a loss of energy, an alteration of ionic homeostasis promoting H 1 and Ca 21 build up and the generation of free radicals. In this context, mitochondria are highly vulnerable and play a predominant role in the cell signaling leading from life to death. This is why, recently, efforts to find an effective therapy for ischemia–reperfusion injury have focused on mitochondria. This review summarizes the pharmacological strategies which are currently developed and the potential mitochondrial targets which could be involved in the protection of cells.  2001 Elsevier Science B.V. All rights reserved. Keywords: Ischemia; Reperfusion; Ca 21 overload; Antioxidant; Mitochondrial transition pore; Mitochondrial metabolism

Contents 1. Introduction ............................................................................................................................................................................ 2. Cellular events mediated by ischemia–reperfusion ..................................................................................................................... 2.1. Ischemia.......................................................................................................................................................................... 2.2. Reperfusion ..................................................................................................................................................................... 3. Pharmacological strategies to protect cells from ischemia–reperfusion injury............................................................................... 3.1. Modulation of mitochondrial metabolism ........................................................................................................................... 3.1.1. Direct effects ......................................................................................................................................................... 3.1.1.1. Trimetazidine ............................................................................................................................................ 3.1.1.2. Ranolazine ................................................................................................................................................ 3.1.1.3. Dichloroacetate ......................................................................................................................................... 3.1.1.4. Carnitine palmitoyltransferase (CPT) inhibitors ........................................................................................... 3.1.1.5. Coenzyme Q 10 ................................................................................................................... 3.1.1.6. Other modulators....................................................................................................................................... 3.1.2. Indirect effects: the Na 1 / Ca 21 exchanger inhibitors ................................................................................................. 3.2. The inhibition of Ca 21 overload ........................................................................................................................................ 3.2.1. Mitochondrial K 1 channel openers ..........................................................................................................................

*Corresponding author. Tel.: 133-1-4981-3661; fax: 133-1-4981-3594. E-mail address: [email protected] (D. Morin). 0169-409X / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0169-409X( 01 )00132-6

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3.2.2. Uncoupler agents ................................................................................................................................................... 3.3. The antioxidant strategy ................................................................................................................................................... 3.3.1. Ginkgo biloba ...................................................................................................................................... 3.3.2. Trans-resveratrol.................................................................................................................................................... 3.3.3. Propofol ................................................................................................................................................................ 3.3.4. Nitrones ................................................................................................................................................................ 3.3.5. Carvedilol.............................................................................................................................................................. 3.3.6. Ebselen ................................................................................................................................................................. 3.3.7. Coenzyme Q 10 and idebenone ................................................................................................................................. 3.4. The permeability transition pore (PTP) as a pharmacological target ..................................................................................... 3.4.1. The effects of cyclosporin A (CsA) ......................................................................................................................... 3.4.2. Coenzymes Q ........................................................................................................................................................ 3.4.3. Other pharmacological inhibitors............................................................................................................................. 4. Metabolic diseases, ischaemia and stress: interactions with mitochondria .................................................................................... 5. The particular case of the preserving solutions for organ transplantation...................................................................................... 6. Conclusions ............................................................................................................................................................................ References ..................................................................................................................................................................................

1. Introduction There are increasing amount of recent evidences that mitochondria are involved in the molecular events leading to the tissue damage occurring in different physio-pathological situations like ischemia, neurodegenerative diseases and basically in the ageing process itself [1–3]. This is particularly true for ischemia which is characterized by an interruption of blood flow and thus, causes a reduction of oxygen availability for the cell. In the absence of oxygen supply, mitochondrial respiration is prevented and ATP synthesis altered. The rupture of the ionic homeostasis induces a depolarization and an accumulation of toxic concentrations of calcium in the cytosol. This is why most of the pharmacological strategies have tried to search for chemical agents able to reduce this ionic disturbance. This gave birth to a wide variety of compounds which protect central or peripheral cells in different animal models of ischemia: the drugs include calcium entry blockers, Na 1 channel inhibitors, N-methyl-D-aspartate receptor / channel (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonists, inhibitors of glutamate release and enhancers of the activity of GABA. Another approach was to inhibit the activation of NO synthase and to scavenge free radical oxygen species (ROS). Although many efforts have been made to develop new drugs, none of them has demonstrated a proven

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clinical efficacy, especially in the field of the neuroprotection. Several reasons have been invoked to explain this failure but the main is probably that all these compounds are capable of inhibiting a specific event of the ischemic cascade but not to protect entirely the cells. To solve this problem, a promising way would be to combine therapy and thus to act on different targets during the same treatment. As underlined by De Keyser et al. [4], this approach would require research conditions unavailable now, for example, agreement between pharmaceutical companies and / or ability to test molecules which are not effective on their own. Nevertheless, the works of Biegon and Bar Joseph [5] and of Chabrier et al. [6] are derived from this idea. They developed interesting molecules which associate two potential protective activities, an antioxidant and a NMDA antagonism in the first case, an antioxidant and a NO synthase inhibitor effect in the second case. Recently, new therapeutic approaches have focused on mitochondrial protection. Several reasons justify this approach. First, whatever the type of ischemia considered, peripheral or central, the physiological events have a common final consequence, the alteration of the mitochondrial functions. Second, mitochondria is the major provider of energy in the cell and it is essential to preserve this function during an episode of ischemia followed or not by a period of reperfusion. Third, mitochondria control intracellular calcium and upon stress generate a high quantity of ROS, two key elements which play a crucial

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role in the evolution of the cell injuries. Fourth, these organelles have been recently shown to coordinate, at least in part, cellular events leading to apoptosis and / or necrosis with the recent discovery that the formation of a pore, generally named permeability transition pore (PTP) may play a pivotal role in cell death [7,8]. The aim of this study is to review briefly the existing marketed antiischemic drugs showing a mitochondrial protecting activity and to discuss the possible mitochondrial targets which could be involved in the protection of cells from ischemia– reperfusion injury.

2. Cellular events mediated by ischemia– reperfusion

2.1. Ischemia Ischemia corresponds to a reduction or a complete blockade of blood flow in a tissue or in an organ (for reviews see Refs. [9,10]), with a rapid loss of oxygen

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supply to the cell. The resulting hypoxia prevents oxidative phosphorylation and, consequently, induces a rapid reduction of the ATP concentration available in the cell, a transient rise in ADP which is degraded and a massive accumulation of phosphate (Fig. 1). The failure of mitochondrial ATP synthesis is temporarily balanced by anaerobic glycolysis which produces lactate and causes a decrease of tissue pH. Glycogen depletion and lactate accumulation increase as a function of the severity of ischemia. When hypoxic conditions persist, the net decrease of ATP concentrations inhibits Na 1 / K 1 ATPase leading to a progressive increase of the concentration of cytosolic Na 1 and a concomitant increase of extracellular K 1 . Na 1 , in turn, activates Na 1 / Ca 21 and Na 1 / H 1 exchanges inducing an accumulation of Ca 21 and protons. The intracellular Na 1 rise results in a depolarization of the cell membrane with transient opening of the voltage-dependent Ca 21 channel increasing Ca 21 flux. In neurons, the entry of cations (Na 1 and / or Ca 21 ) is also mediated by the three major types of ionotropic glutamate receptors N-methyl-D-aspartate, AMPA and kainic

Fig. 1. Scheme representing mitochondrial alterations during ischemia reperfusion. DC, mitochondrial membrane potential; PTP, permeability transition pore; RC, respiratory chain; ROS, radical oxygen species.

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acid, which are activated by the release, and failure of reuptake, of excitatory amino acids, especially glutamate, in the synaptic cleft [11,12]. However, as the mitochondria are at least partially de-energized, mitochondrial Ca 21 accumulation may not be severe. Taken together, anaerobic glycolysis, nucleotide hydrolysis and the release of protons from acidic organelle cause a drop of cytosolic pH by a unit or more [13]. This acidosis, associated with a low mitochondrial Ca 21 concentration, protects strongly against the ischemic injury [14] and prevents the opening of the mitochondrial transition pore [15,16] although favorable opening conditions prevail (high Pi, decrease ATP and ADP). However, prolongation of ischemia leads cells to a point of no return beyond which the cellular damages become irreversible and the cell die. The length of the ischemic period to cause cell death depends on the organ and on the cell type. In the same way reperfusion corresponding to the readmittance of oxygen to the cell can paradoxically accelerate tissue necrosis [17].

2.2. Reperfusion Reperfusion corresponds to the restoration of oxygenated blood flow to the ischemic tissue. This situation is encountered clinically in thrombolysis, by-pass surgery and organ transplantation. At the mitochondrial level, it is characterized by the recovery of the activity of the respiratory chain which restores the membrane potential and may drive the elevated cytosolic calcium into the mitochondria to the detriment of ATP synthesis (Fig. 1) [18–20]. Mitochondrial Ca 21 overload per se is not a condition which induces cell injury. Indeed, mitochondria are able to accumulate high Ca 21 concentration if enough ATP and ADP are supplied and if matricial pyridine nucleotides are maintained in reduced state. However, the sudden influx of oxygen also leads to a burst of ROS, which induces oxidative stress [21] and deplete mitochondrial pyridine nucleotides and glutathione, reducing compounds protecting mitochondria against oxidative insults. All these conditions favour the mitochondrial pore opening which cause swelling, collapse of membrane potential and in fine total inhibition of mitochondrial functions [8,22].

These pathological insults cause necrotic cell death but it has been increasingly recognized that they can also induce apoptosis [23–26]. The nature of the death would depend on the intensity of the insult and on the ability to maintain ATP synthesis. In the core of the infarct, cells rapidly loss ATP and die by necrosis whereas peripheral cells continue to produce ATP and are able to execute the apoptotic process [27], although in the CNS there is a spectrum between the two modes of cell death, depending on the cell type and local conditions [28].

3. Pharmacological strategies to protect cells from ischemia–reperfusion injury From mild to severe ischemia, the mitochondrial successive alterations include a deficit of the metabolism, an oxidative stress, a Ca 21 overload, the generation of the PTP leading to mitochondrial swelling and necrotic and / or apoptotic cell death. An increasing number of pharmacological approaches are actually developed to try to interfere with these mitochondrial steps. They are briefly reviewed in this section and summarized in Fig. 2.

3.1. Modulation of mitochondrial metabolism As mitochondrial alterations appear to determine the progression of cell injury to a state of irreversibility, the modulation of the mitochondrial metabolism is the object of growing interest, especially for cardiac ischemia. The aim of this approach is a best use of the available substrates during the ischemic process to minimise the injury and to rescue tissues. This pharmacological strategy has been applied with success in the moderate or mild myocardial ischemia in Angina pectoris. The strategy is less effective in the face of complete ischemia. In normoxic conditions, cardiac cells mainly use the fatty acid pathway to generate ATP (70%) when 30% comes from the utilization of glucose. During ischemia nearly all ATP is produced by the oxidation of fatty acids or by anaerobic pathways. Now the fatty acid pathway is less efficient (produced ATP/ consumed oxygen55.2) than the glucidic one (ATP/ O56; [10]) and this contributes to increase the ATP deficit.

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Fig. 2. Mitochondrial sites as targets for antiischemic drugs. 1, activating effect. 2, inhibiting effect; CPT, carnitine palmitoyltransferase; DCA, dichloroacetate; PDH, pyruvate dehydrogenase; PTP, permeability transition pore; ROS, radical oxygen species.

In addition, when ischemia pursues, the degradation of fatty acid induces an accumulation of acetylcoenzyme A which inhibits both pyruvate dehydrogenase (PDH), the enzyme responsible for the catabolism of pyruvate, and the enzymes of the beta-oxidation. This reinforces the inhibition of the glucose pathway and increases the cytosolic accumulation of lactate and protons from pyruvate and thus the acidosis. The levels of acylCoA and acylcarnitine also raise and they are deleterious for mitochondrial and plasma membranes [29]. Thus, metabolic mitochondrial disorders are doubly baneful: First, because the lipid metabolites which

accumulate are deleterious for the cell and secondly because the efficiency of ATP synthesis is low, mitochondria consuming more oxygen to produce ATP than in normoxic conditions although the quantity available is limited. Pharmacological approaches have been found to redirect mitochondrial metabolism in order to favor glucose oxidation to the detriment to fatty acid catabolism. This would theoretically lead to a greater ATP/ oxygen yield, a greater rate of pyruvate oxidation and, thus, a decrease of lactate accumulation. This approach is particularly relevant for organs using mainly fatty acid as a substrate. Several drugs,

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i.e. etomoxir, ranolazine were developed according to this idea but up to now the only marketed drug available is trimetazidine.

3.1.1. Direct effects 3.1.1.1. Trimetazidine Trimetazidine (1-[2,3,4-trimethoxy-benzyl]piperazine, 2 HCl) is registered since 1978 and marketed in a number of countries as a safe cellular antiischemic drug devoid of hemodynamic effects. Although the clinical efficacy of trimetazidine was demonstrated in several double blind trials and its antianginal effect was shown to be equivalent to propranolol in a multicenter European trial (for a review see Ref. [30]), the molecular mechanism of its antiischemic effect was not fully understood until recently. Different hypotheses which are not mutually exclusive have been proposed. A common feature of these hypothesis is that trimetazidine improves energy metabolism and ATP synthesis in different in vitro and ex-vivo models of myocardial and liver ischemia [31–34]. One of them involves a switch of the cellular metabolism towards glucose utilization at the expense of lipid metabolism. This was suggested by the work of Fantini et al. [35] who showed that trimetazidine was able to inhibit palmitoyl-carnitine oxidation on rat cardiomyocytes. Identical results were found in ischemic isolated hearts perfused with fatty acid: trimetazidine reduced the deleterious increase in acyl carnitine levels induced by ischemia [36]. This effect is not due to a direct inhibition of palmitoyl-carnitine transferase 1 (CPT-1), which transports palmitoyl carnitine across mitochondrial membranes, since trimetazidine was without effect on this enzyme [37]. On the other hand, trimetazidine does not inhibit the accumulation of long chain acylCoA level. This reduction of fatty acids oxidation was associated with a decrease in the activity of the long-chain isoform of the last enzyme involved in fatty acid oxidation, 3-ketoacylcoenzyme A thiolase [38]. This effect occurred at low trimetazidine concentrations (IC 50 575 nM) and is accompanied by an increase in glucose oxidation. This latter effect is not due to a direct enhancement of PDH activity but to a decrease of the inhibiting effect caused by the accumulation of acetylCoA. Thus, 3-ketoacylcoenzyme A thiolase

appears as a potential target for trimetazidine: furthermore, enzyme inhibition is only partial so lipid oxidation is not completely inhibited. Whether this mechanism of action is relevant for short or mild ischemia, it seems difficult to explain entirely the pronounced protective effect we observed after a total prolonged liver ischemia (2 h) followed by 30-min reperfusion [34]. Other mechanisms have been suggested which include a reduction of ionic imbalance [39]. Indeed, we recently showed that trimetazidine can cross cellular membranes transferring protons from an acidified cellular compartment to the extracellular space [40]. Altogether these data clearly indicate that mitochondria is the main target of the drug. One can suppose that the overall protective effect corresponds probably to a combination of the different properties of the drug according to the severity of the ischemia.

3.1.1.2. Ranolazine Ranolazine has shown cardiac anti-ischemic activity in several in vitro and in vivo animal models and antianginal properties in clinical trials [41,42]. It does not affect hemodynamics or baseline contraction and, thus, like trimetazidine, offers the opportunity to treat angina without reducing blood pressure, heart rate and myocardial contractility. Clarke et al. [43] were the firsts to observe a prevention by the drug of the reduction in the amount of active PDH during the ischemic period. This protective effect was first thought to result from a direct action of the drug on the enzyme but several studies failed to demonstrate any effect of the drug on PDH kinase or phosphatase, or on PDH catalytic activity [44]. At the present time, the prevailing hypothesis is an inhibition of fatty acid metabolism, probably partly by limiting the effect of palmitoyl-L-carnitine [45], leading to a decrease of acetylCoA and an indirect stimulation of PDH, a trimetazidine like profile. Ranolazine is in phase III clinical trials as an antianginal agent and for the treatment of peripheral arterial disease. 3.1.1.3. Dichloroacetate Another way to promote carbohydrate oxidation is to stimulate directly PDH. This enzyme is a complex protein including three major subunits that catalyze the oxidation of pyruvate to acetylcoenzyme A. PDH

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phosphatase dephosphorylates and stimulates the enzyme whereas PDH kinase inhibits it. Dichloroacetate inhibits PDH kinase and maintains PDH in its active, phosphorylated form, enhancing pyruvate oxidation [46,47]. The beneficial effect of dichloroacetate can also be due to its ability to decrease cytosolic acidosis that alters ionic homeostasis and lead to Ca 21 accumulation and mitochondrial damage during reperfusion. Indeed, the increase in pyruvate oxidation may promote lactate elimination thereby increasing cellular pH. Such a change has been observed in patients during a dichloroacetate treatment [48]. The beneficial effect on ischemia and reperfusion has been demonstrated in isolated perfused rat heart [49,50] and in the intact animal [51]. Few short-term clinical studies have been performed but they confirmed the effectiveness of the drug in patients with myocardial ischemia or heart failure [48,52,53]. Clinical data indicate that the effect does not result from an hemodynamic modification or an increase of oxygen consumption but from an improvement of substrate utilization. It should be noted that dichloroacetate also improved indices of both brain cerebral metabolism and neuronal and glial functions in patients affected by various primary mitochondrial disorders [54]. Long-term clinical studies are lacking but short-term administration appears to be safe. Unfortunately, the development of dichloroacetate is limited by a short half-life, and because high blood concentrations (millimolar) are required to obtained an effect and certainly also because it is not under patent protection, as suggested by Stanley et al. [10].

3.1.1.4. Carnitine palmitoyltransferase ( CPT) inhibitors Another way explored to modulate mitochondrial metabolism is inhibition of CPT-1. This enzyme located on the mitochondrial outer membrane is responsible for long chain acyl carnitine formation. Its inhibition occurs upstream to the beta-oxidation, reduces fatty acids oxidation and induces a secondary increase in glucose utilization [55,56]. This effect protects heart from ischemic injury in vitro. This was demonstrated with the CPT-1 inhibitors etomoxir [57], sodium 2-(5-(4-chlorophenyl)pentyl)-oxirane-2-carboxylate [58] and oxfenicine [58–60] which is converted to the active CPT-1

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inhibitor 4-hydroxy-phenylglyoxylate. However, long-term treatment with such drugs revealed a cardiotoxicity which hampered their clinical use [61]. A recent study reactivates this approach. Indeed, two well-known anti-anginal agents perhexiline and amiodarone were shown to produce a concentration-dependent inhibition of CPT-1 [62]. The IC 50 of these drugs are relatively high, 77 and 228 mM for perhexiline and amiodarone, respectively, but these drugs are known to be highly concentrated in the tissues and particularly in mitochondria [63,64]. So this effect is likely to contribute to the anti-ischemic effect of these two drugs and provide an explanation for the ability of perhexiline to decrease fatty acid oxidation in favor of glucose oxidation, thereby increasing cardiac efficiency [65].

3.1.1.5. Coenzyme Q 10 Coenzymes Q are a group of lipid-soluble benzoquinones involved in the electron transport in mitochondria. The endogenous occurring member is coenzyme Q 10 (ubiquinone 50) which is a lipid mobile constituent of the respiratory chain and acts as an electron shuttle between complex I (oxidation of NaDPH), complex II (oxidation of succinate) and the cytochrome system of the complex III [66]. Exogenous administration of coenzyme Q 10 was shown to improve myocardial functions in rats with chronic heart failure [67] and during postischemic reperfusion [68]. Coenzyme Q 10 is an effective blocker of lipid peroxidation but its protective mechanism during ischemia–reperfusion seems to be mostly independent from this antioxidant effect. Indeed, coenzyme Q 10 neither scavenged the primary burst of superoxide or hydroxy radical generation when it was delivered immediately before reperfusion nor reduced the total free radical generation during this period [69]. The protective effect of this compound probably results from a multifactorial mechanism including a recovery of ATP and phosphocreatine concentrations initially and during reperfusion, and a protection of creatine kinase during reperfusion [69,70]. Coenzyme Q 10 is commercialized as a drug in Japan and Italy and several studies have demonstrated clinical improvement in patients with congestive heart failure, ischemic heart disease and reperfusion injury [71,72].

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3.1.1.6. Other modulators A number of other compounds have been used to try to improve energy metabolism during ischemia. All are substrates or cofactors of key enzymes of the mitochondrial metabolism. The list includes L-carnitine, pyruvate, succinate, sulbutiamine, riboflavine, thiamine and menadione (for reviews see Refs. [73– 75]). Most of these drugs were shown to reduce ischemic injury in a number of experimental model systems and may improve the clinical outcomes of patients. However, the potential utility and use of these therapeutic interventions is hampered by the absence of serious controlled clinical trials. 3.1.2. Indirect effects: the Na 1 /Ca 21 exchanger inhibitors Ca 21 enters mitochondria through an electrophoretic uniporter that is driven by the inner membrane potential and is released by different ways involving two specific exchangers: Na 1 / Ca 21 and H 1 / Ca 21 . The major egress pathway is independent of Na 1 in non-excitable tissues while Na 1 / Ca 21 exchange predominate in mitochondria from excitable tissues [76]. They maintain an appropriate Ca 21 concentration in the mitochondrial matrix. Three Ca 21 sensitive matrix dehydrogenases modulate mitochondrial metabolism, PDH, isocitrate and alpha-ketoglutarate which both catalyse reactions within the Krebs cycle [77]. Within the range 0.2–2 mM, Ca 21 activates these enzymes and consequently the overall rate of ATP synthesis. Thus, increasing free matricial concentration might constitute another way to improve energy metabolism and may be beneficial in some pathological situations as acute myocardial ischemia. This may be obtained by decreasing the efflux of Ca 21 from mitochondria. Such an approach was suggested 10 years ago [78]. Certain Ca 21 antagonists and benzodiazepines were found to inhibit Na 1 / Ca 21 exchanger activity. Diltiazem and clonazepam were the most potent with IC 50 values in isolated heart mitochondria in the mM range. This property has been suggested to play some role in the cardioprotective effect of the drug. According to this observation, Chiesi et al. [79] identified a new benzothiazepine CGP37157 which was more potent (activity in the submicromolar range) and, especially more specific than the other drugs, having no effect on the major mechanisms

which regulate cellular Ca 21 level. CGP37157 stimulated both the rate of NADH formation and ATP production and these effects were directly related to Na 1 / Ca 21 exchange inhibition [78]. However, to our knowledge this elegant approach did not progress to a clinical study and has been abandoned but CGP37157 remains a useful tool to study Ca 21 signal transmission in the cell.

3.2. The inhibition of Ca 21 overload As discussed above, ischemia and more particularly reperfusion lead to a massive Ca 21 accumulation which, under conditions of oxidative stress, culminates in an increase of membrane permeability and an impairment of mitochondrial functions. Ca 21 loading plays a crucial role in this phenomenon and its limitation represents a relevant objective. Consistent with this hypothesis is the observation that chelation of Ca 21 or inhibition of mitochondrial uniporter by ruthenium red protects hearts against oxidant stress and ischemia–reperfusion injury [80– 82]. Mitochondrial membrane potential is a critical regulator of the mitochondrial capacity to accumulate Ca 21 and this prompted to consider the decrease of the potential as a possible mechanism of cellular protection. This profile of action is observed with K1 ATP channel openers and uncoupler agents.

3.2.1. Mitochondrial K 1 channel openers Inoue et al. [83] were the first to demonstrate the existence of K 1 ATP channels in the inner membrane of liver mitochondria (for recent reviews see Refs. [84,85]). These channels were found in heart and in brown adipose tissue and share some common 1 properties with the sarcolemmal K ATP channel. The channels have a pharmacological distinct profile. 5-Hydroxydecanoate inhibited K 1 flux in mitochon1 dria but failed to block the sarcolemmal K ATP channel under any experimental conditions. In the same way, the K 1 ATP channel activator diazoxide is 2000-times more potent in opening the mitochondria 1 K1 ATP channel than in opening the sarcolemma K ATP channel [86]. The sole known function of the mitochondrial K 1 cycle is the regulation of the matrix volume [87].

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Mitochondrial K 1 ATP channels are regulated by several endogenous compounds and recently, Holmuhamedov et al. [88] provide evidence that mitochondrial K 1 ATP channel openers modulate functions vital for cardiac mitochondria. They demonstrated their implication in the induction of membrane depolarization, the alleviation of ATP production, the induction of swelling and the release of accumulated Ca 21 and intermembrane proteins. Using diazoxide, Garlid et al. [89] observed a cardioprotective effect of the drug in an isolated rat heart model of ischemia–reperfusion. This effect was completely abolished by the selective inhibitor 5hydroxydecanoate, excluding a role of the sarcolemma K 1 ATP channel in ischemic protection. The cardioprotective effect of diazoxide was confirmed in another model of ischemia [90,91] supporting the hypothesis that cellular protection afforded by some K 1 openers may be mediated by their interaction with mitochondria. Diazoxide restored myocardial ATP and creatine phosphate and attenuated the decrease in mitochondrial oxygen consumption at the end of ischemia as well as at the end of the reperfusion [91]. How might opening of mitochondrial K 1 channels protect the cell ? The beneficial effect could be the consequence of the net influx of K 1 which causes a partial dissipation of the membrane potential [92]. This would prevent or release an excess of Ca 21 accumulation [93]. However, activation of these channels was also shown to cause a decrease of ATP synthesis and a release of cytochrome c in the cytosol [88], two events which have been associated with the induction of apoptosis [8]. It should be also noted that the membrane potential modulates PTP opening [94] which is implicated in the pathogenesis of necrotic and apoptotic cell death [95]. The net mitochondrial effect of these drugs (protective or deleterious) is therefore difficult to predict but the convincing results obtained with diazoxide are very stimulating. Targeting mitochondrial K 1 ATP channel provides a useful approach to protect cells from disease conditions associated with metabolic alterations, especially ischemia–reperfusion. The development of this concept will need new specific agents to dissect the mechanism of cardioprotection and to extend this research to other organs.

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3.2.2. Uncoupler agents Uncoupling is the result of an increase of the H 1 permeability across the inner mitochondrial membrane. Uncoupling agents, such as 2-4-dinitrophenol (DNP) dissipate the proton gradient of the mitochondrion and thus oxidative energy is wasted as heat. DNP was used as a slimming aid in the 1930s. Fatty acids, thyroid hormones and several synthetic compounds are protonophorous uncouplers [96]. This effect is mediated by specialized proteins termed uncoupling proteins which were first discovered in brown adipose tissue (for review see Ref. [97]) and are responsible for thermogenesis, particularly during hibernation. Other proteins as the ADP/ATP antiporter (ANT) were also suggested to have uncoupling properties. A pronounced lasting uncoupling is baneful for mitochondria. Indeed, it was demonstrated to kill cells [98] and could be one of the components of the mechanism of action of several anticancer drugs causing PTP opening and apoptosis [99,100]. In addition, an increase of proton leak as well as an inhibition of the respiratory chain have also been suggested to contribute to ischemic heart alterations [101]. This might be caused by the generation of ROS inducing damage to the mitochondrial membrane, especially complex I. Meanwhile, recent data suggest that a mild uncoupling of mitochondria might be an interesting defense strategy to limit the mitochondrial damage generated by oxidative stress. This idea was developed by Skulachev’s group who demonstrated a close relationship between the mitochondrial membrane potential and ROS production [102]. They showed that a high transmembrane electrochemical potential of H 1 is dangerous for the cell since it increases the probability of ROS formation. He proposed to induce a proton leak across the inner membrane in order to increase oxygen consumption and thus to lower both the electrochemical potential of H 1 and ROS production. A similar effect was obtained by addition of malonate which inhibits complex II and decreases the respiration rate [103], indicating that both an increase or a decrease of oxygen consumption might inhibit ROS formation. This shows that ROS formation is function of the membrane potential rather than the electron transport rate in the respiratory chain and recent data support

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the hypothesis that uncoupling proteins could regulate ROS generation [104]. Thus, mild uncoupling may represent an antioxygen defense mechanism during the reperfusion period, preventing the sudden increase of membrane potential but also limiting Ca 21 entrance into mitochondria. This is in line with the results of Nicholls and Budd [105] who demonstrated that mitochondrial depolarization (and hence inhibition of mitochondrial Ca 21 accumulation) strongly protect cultured cerebellar granule cells against glutamate toxicity. In summary, a preventive mild uncoupling would limit the two principal deleterious mitochondrial phenomena occurring during ischemia-reperfusion, Ca 21 overload and ROS production. Actually, none marketed drug fulfill these criteria but it is a promising field of research where uncoupling proteins appear as interesting targets.

3.3. The antioxidant strategy Mitochondria are the main site of free radical production in the cell. This is a physiological event under aerobic conditions. ROS are mainly produced at the level of complex I and complex III of the respiratory chain [106]. In normal conditions only about 2–4% of the oxygen consumed is released in the mitochondrial matrix as a superoxide radical ?2 (O ?2 2 ). O 2 , following dismutation, can give birth to the radical hydroxyl (OH ? ) which is highly cytotoxic. Moreover, O ?2 2 can react with nitric oxide inside mitochondria to yield damaging peroxynitrite. In normal conditions, ROS are eliminated by a very efficient antioxidant system constituted by a group of enzymes, glutathione reductase (GR), glutathione peroxidase (GP), superoxide dismutase (SOD) and the NADPH transhydrogenase and vitamins C and E. The efficiency of these protecting systems declines with age and as the leak of ROS from the respiratory chain is more pronounced (loss of electron transfer chain activity), there is a general agreement to think that the oxidative damages caused by ROS could be, at least in part responsible for ageing as well as for neurodegenerative diseases [107,108]. Mitochondrial oxidative stress is also a major component of the acute ischemia–reperfusion process. It is generally considered that ischemia does not promote ROS

production since hypoxia slows down or stops the electron transfer chain activity. This probably depends on its degree (complete or partial) and on its duration. Indeed, some in vitro studies [20,109] clearly indicate that increasing the duration of ischemia reduces the protective mechanisms against oxygen toxicity (decrease SOD activity and GSH content), with a concomitant increase in ROS production. This could be partly due to the slight rise of Ca 21 occurring during hypoxia [19] since Ca 21 potentiates ROS production [110]. Reperfusion amplifies the phenomenon and emphasizes mitochondrial alterations. As pointed out before, the reactivation of the respiration at the beginning of the postischemic reperfusion induces a burst of O 2?2 which cannot be eliminated. In addition, ROS production is exacerbated by Ca 21 that accumulates during reperfusion [111,112]. ROS are potentially very damaging for mitochondria causing oxidation of lipids that could disturb the lipid bilayer permeability essential for oxidative phosphorylation, oxidation of proteins that could alter their activity and oxidation of bases in mitochondrial DNA which could modify its products. The radical hydroxyl OH ? can generate toxic lipid peroxide products such as malondialdehyde, 4-hydroxynonenal and can also attack directly protein residues, like –SH groups, which have been involved in PTP opening [113]. So protecting mitochondria against the oxidative stress mediated by the ischemia–reperfusion is a major objective. There are two main ways to protect mitochondria against oxygen toxicity. The first one is to prevent the formation of ROS (see previous paragraph) but when it failed, the second way consists in eliminating the toxic oxygen intermediates already formed. The next sections display natural and / or marketed compounds exhibiting these properties.

3.3.1. Ginkgo biloba Ginkgo biloba extracts are obtained from the fruits and the leaves of the tree Ginkgo biloba and have been used therapeutically for centuries in traditional Chinese medicine. A highly refined extract (EGB 761, bilobalide) has been used in France and in Germany to treat peripheral vascular and neurological disorders since more than 20 years. Indeed, this extract has been shown to have cardioprotective and

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neuroprotective effects (for review see Refs. [114,115]) and to be effective in the prevention of ischemia–reperfusion injuries [116,117]. Its mechanism of action is not well-defined but it is evident now that some of its protective effect can be attributed to direct radical scavenging properties since bilobalide, which contains flavonoids, organic acids and terpernoids, has been reported to scavenge hydroxyl, superoxide, peroxyl and nitric oxide radicals (for review see Ref. [118]). Recently, a mitochondrial target was evoked to explain the beneficial role Ginkgo biloba against ischaemic injury. Seif-ElNasr and El-Fattah [119] demonstrated that Ginkgo biloba extract reduced the lipid peroxide and phospholipid content of rat brain mitochondria. In the same way Ginkgo biloba extract was shown to protect mitochondrial respiratory activity and to restore oxidative phosphorylation efficiency impaired by hypoxia and anoxia / reoxygenation [120,121]. This effect may be due to the protection of complex I activity [122] which was related to the scavenging of superoxide generated during the reoxygenation phase [121]. Indeed complex I activity declines during ischemia–reperfusion [123] and may result in an overproduction of free radicals as inhibition of complex I in vitro promotes free radical generation. In this hypothesis the antiischemic effect afforded by bilobalide would be, at least in part, the consequence of its antioxidant properties improving mitochondrial functions and aging [3]. It must be underlined that bilobalide protects mitochondrial P450 side chain cleaving, the enzyme responsible for the cleavage of cholesterol to pregnenolone, and regulates glucocorticoid synthesis [124,125]. This may also participate to its neuroprotective mitochondrial effects.

3.3.2. Trans-resveratrol Trans-resveratrol is a phytoalexin found in various plants and in some red wines. Its presence in these wines explains the apparent paradox of the beneficial effect of long-term moderate wine intake in various pathological states including ischemic heart disease [126,127]. Its antioxidant properties are related to its polyphenol structure associated with a double bond [128]. Trans-resveratrol is a free radical scavenger and is able to inhibit lipid peroxidation [129]. Interestingly, trans-resveratrol also prevented the

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formation of O ?2 in a preparation of mitochondria 2 isolated from rat cerebral cortex. This effect was due to the inhibition of complex III activity and more specifically to an interaction with the decylubiquinone cycle. It should be emphasized that this effect is only partial (220% at 1 mM) and did not suppress mitochondrial respiration whereas the total complex III blocker antimycin A stopped oxygen consumption and amplified O 2 2 production [129]. The fact that ROS are mainly generated at complex III may explain why trans-resveratrol, by decreasing complex III activity, may limit the damage caused by ischemia–reperfusion. Therefore, trans-resveratrol combines two beneficial properties, a pure antioxidant and a mild uncoupling (inhibition of complex III) activity. Trans-resveratrol was also shown to inhibit ATPase activity [129]. This could reinforced the beneficial effect of the drug since prevention of ATP depletion protects against cell killing in different model of hypoxia or ischemia [98,105,130].

3.3.3. Propofol Propofol is a general anesthetic which has a chemical structure close to the nucleus of wellknown antioxidant substances as alpha-tocopherol. It has been demonstrated to protect different tissues from oxidative injury [131–133] and to be neuroand cardio-protective in several models of ischemia– reperfusion [134–137]. The mechanism of protection is attributable to the antioxidative property of propofol which is well established [138,139]. Eriksson [140] was the first to suggest that the protective effect of propofol could be, at least in part, related to the protection of mitochondrial function. He showed that propofol inhibited PTP opening in rat liver mitochondria by scavenging free radicals. These results were confirmed in a heart model of ischemia– reperfusion: propofol conferred a significant protection and it was associated with a decrease of PTP opening [137,141]. However, its antioxidant activity is probably not the only mechanism responsible for PTP closure. Indeed, propofol has also a complex uncoupler profile which probably contributes to the mitochondrial effect [142,143]. It is certainly an interesting drug that Javadov et al. [137] proposed to add to cardioplegic solutions in heart surgery.

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3.3.4. Nitrones Nitrones have long been known to interact with mitochondria and modify cell function. Structure– activity of a series of nitrones at mitochondria was shown to correlate with smooth muscle relaxant effects [144], but nitrones have also recently been shown to have sufficiently powerful antiischaemic effects to merit testing in clinical trials. Nitrones may function as spin traps of free radicals, and 2,29pyridylisatogen (Fig. 3) [145] has been recently reported to form a highly stable adduct with free radicals [146]. This compound interferes with the mitochondrial permability transition [147] and is protective against glutamatergic-induced neural cell death in vivo (manuscript in preparation). Glutamateinduced neuronal cell death requires mitochondrial calcium uptake [148] and the mitochondrial permeability transition is a key factor (see below). Thus nitrones may be powerful neuroprotective agents. In this respect, N-t-butyl-a-phenyl-nitrone (tBPN) is a potent spin trapping agent which is highly active in global and focal ischaemia models [149–151]. New compounds such as NXY-059 are in evaluation for use in stroke [152]. 3.3.5. Carvedilol Carvedilol is a vasodilating adrenoceptor antagonist, possessing both a1- and b-adrenergic blocking properties (for review see Ref. [153]), which protects myocardium against ischemic and lethal reperfusion injury [154,155]. The drug also possesses antioxidative properties [156] and has been shown to prevent the lipoperoxidation of mitochondrial membranes [157]. In addition, carvedilol was recently shown to inhibit NADH dehydrogenase [158], an enzyme located in the outer leaflet of the inner mitochondrial membrane, that has been shown to promote ROS

Fig. 3. Structure of nitrone compounds.

release under conditions of ischemia–reperfusion [159]. This could also contribute to the protection of the mitochondrial energetics during oxidative stress. Thus, carvedilol is an original drug which joins together the classical property of a b-antagonist agent and an antioxidant activity associated with protection of mitochondrial functions.

3.3.6. Ebselen Another approach to assist the antioxidant defensive system is to activate the enzymes responsible for ROS trapping or to mimic their effect. This is achieved by ebselen (2-phenyl-1,2-benzisoselenazol3(2H )-one), a non-toxic seleno-organic drug with antiinflammatory, antiatherosclerotic and cytoprotective properties that mimics the catalytic activities of phospholipid hydroperoxide glutathione peroxidase [160]. It has been shown to be a potent neuroprotective compound in stroke in humans [161] and in rodents [162,163] but also to prevent tissue injuries during heart [25], liver [164] and gastric [165] ischemia–reperfusion. A microdialysis study indicates that ebselen limits cerebral metabolic changes during ischemia (decrease of lactate accumulation) and accelerate the recovery during reperfusion [166]. The effect of ebselen on mitochondria was little studied. Moreover, the agent was demonstrated to protect liver mitochondria from lipid peroxidation, induced by iron / ascorbate and iron / citrate [167,168]. This effect was associated with an inhibition of the release of the apoptogenic factor cytochrome c [169] but does not seem to involve a blockade of PTP opening [168,169] although opposite results have been reported [170]. Altogether these data suggest that the cytoprotective effect of ebselen during ischemia–reperfusion may be due in part to its antioxidant properties at the mitochondrial level. 3.3.7. Coenzyme Q 10 and idebenone As specified before (Section 3.1.1.5.), the antiischemic properties of coenzyme Q 10 were not considered to result from its antioxidant effect. A derivative of coenzyme Q, idebenone which is able to transfer electron inside the respiratory chain was also studied. In vitro and in vivo studies suggest the drug may diminish nerve cell damage due to ischaemia, correct neurotransmitter defects and / or cerebral metabolism

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and facilitate memory and learning [171]. However, its development was stopped because it did not show sufficient efficacy in the treatment of Alzheimer’s disease.

3.4. The permeability transition pore ( PTP) as a pharmacological target PTP is a fast increase of permeability of the mitochondrial membrane which causes membrane depolarization, release of matrix molecules of molecular mass less than 1500 Da, uncoupling oxidative phosphorylation and swelling [7]. This phenomenon was first described by Hunter and Haworth [172,173] and is now considered to be the consequence of the formation of a pore. The first important step in the characterization of PTP was the discovery that the immunosuppressant drug cyclosporin A (CsA) was able to retain mitochondrial Ca 21 [174] at very low concentrations and thus to inhibit PTP opening [175]. The second one was the identification in the inner mitochondrial membrane of a high conductance channel whose opening appeared responsible for PTP [176]. Whereas a controversy persists concerning the molecular composition of this pore, inner membrane adenine nucleotide translocator (ANT) modulated by a cyclophilin (CyP-D) as suggested by Halestrap and Davidson [177] or multiproteic structure located at the level of the contact sites between the inner and the outer mitochondrial membrane including porin, hexokinase, creatine kinase, ANT and CyP-D [178], there is now a good agreement to consider PTP as a crucial event leading to cell death by necrosis or apoptosis (for recent reviews, see Refs. [8,95,179]. Crompton et al. [180] were the firsts to suggest that PTP might be involved in the pathogenesis of necrotic cell death following ischemia–reperfusion. Indeed, they noticed that all cellular conditions which promote PTP (Ca 21 overload, high Pi concentrations, oxidative stress) prevail during ischemia–reperfusion. This hypothesis was recently reinforced when it was shown that PTP opening might control apoptosis by causing release of apoptogenic factors which activate caspases [181] and is regulated by the pro- and the anti-apoptotic members of the Bcl-2 family [182,183]. A new pharmacological strategy appears from

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these data. The idea is that if PTP is a key event in the genesis of cell death following ischemia–reperfusion, molecules which are able to inhibit PTP would probably help the cell to recover. CsA provided the first evidence that this strategy is relevant. It should be mentioned here that a recent observation suggests that caspase-3 activity can be stimulated directly in the first time of the ischemia before any detectable occurrence of PTP and any increase of caspase-9 activity, though located upstream caspase-3 in the activation cascade [184]. This gives another opportunity for a pharmacological intervention but this is not the subject of this review.

3.4.1. The effects of cyclosporin A ( CsA) CsA was the first drug shown to inhibit PTP and up to now this is the most potent. It is generally assumed that CsA binds to a mitochondrial cyclophilin (CyP-D) with nanomolar affinity and prevents the interaction of this protein with ANT thus inhibiting pore opening [178,185]. Shortly after the identification of CsA as a PTP inhibitor, several reports demonstrated that CsA prevented or delayed cell death in different models of oxidative stress [186–188]. However, there was no evidence of a direct link between the inhibition of PTP and the protection of cells. Different elegant approaches were used to address this question. First, the immunosupressive effect of Csa was dissociated from its mitochondrial interaction. A 4-substituted analogue of CsA lacking immunosuppressive property (no inhibition of calcineurin) was shown to be as active as CsA at inhibiting the pore [16]. Then, Lemasters’s group used laser scanning confocal microscopy to visualize the increase of mitochondrial membrane permeability within cells. Cells were loaded with fluorescent dyes which accumulate electrophoretically into mitochondria and provided a good index of the membrane potential [189]. Hypoxia and oxidative stress caused a collapse of the potential as indicated by the modification of the distribution of the dyes. CsA prevented these events and protected the cells [190]. CsA also protected brain and heart from ischemia– reperfusion [191–193]. Griffiths and Halestrap [192] have developed a perfusion technique using a radiolabelled marker [ 3 H]2-deoxyglucose to monitor PTP opening in the isolated rat heart during ischemia–

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reperfusion. This study revealed that the pore remained close during 30 min ischemia and open upon reperfusion. Pretreatment of the organ with submicromolar concentrations of CsA prevented pore opening, improved the recovery of heart during reperfusion but did not counteract the impairment of the respiratory chain function as measured by the activity of ATP synthase [192,194]. This alteration is probably due to the accumulation of ROS during ischemia and reperfusion [195]. Taken together, these experiments established clearly that PTP is a critical event in the genesis of cell injury generated by ischemia–reperfusion in different peripheral organs and that CsA protects cells by inhibiting PTP during reperfusion. It does not mean that other mechanisms are not involved in the protective effect of CsA and this is particularly obvious in the brain where a definite role of PTP in cell death is less clear [196]. Consistent with the presence of PTP in brain are the experiments realized on isolated mitochondria [197,198], the observations that CsA delayed glutamate-induced mitochondrial depolarization [199] and that its neuroprotective effect in a hypoglycemic rat model implicated PTP [200]. However, strong evidences support the hypothesis that the ability of CsA to protect neuronal cells does not result exclusively from inhibition of PTP. Indeed, the Ca 21 -calmodulin-dependent phosphatase calcineurin might play a major role in the induction of neuronal death [201] and calcineurin inhibition could explain the neuroprotective effect of immunosuppressive drugs in focal / cerebral ischemia [202]. This idea was reinforced by the fact that a protecting effect against reperfusion injury was ascertained with the calcineurin inhibitor FK506 in heart and brain [203,204] while this drug did not inhibit PTP generation [205]. Thus, the existence of PTP in brain cells and, its involvement in the neuroprotective properties of CsA, which have been demonstrated in several models, is still a source of debate. Its occurrence seems to be highly dependent from the experimental in vitro conditions, from the brain cell and region considered and from the ischemic model used in vivo [198,206]. At the present time one must conclude that the cellular protective effect

of CsA may result from both PTP and non PTPdependent mechanisms. However, both pharmacokinetic and pharmacodynamic parameters argue against the clinical used of CsA in ischemia. The drug targets at least eight other cyclophilins in the cell whose roles are largely unknown and they are likely to bind most of the drug. Thus, the mitochondrial concentration of CsA is difficult to predict and a CsA treatment may require high, and even toxic, concentrations to reach the mitochondrial target. In addition, the biotransformation of CsA may give birth to inactive metabolites towards PTP as observed with N-desmethyl-4CsA [16]. Moreover, in in vitro experiments, the protecting effect of CsA is only transient when mitochondrial swelling is generated by Ca 21 overload in the presence of an oxidative stress. CsA slows down the swelling but finally amplifies the phenomenon. Different hypothesis have been raised to explain this deleterious effect [207,208] and there is good evidence that CsA is able to cause oxidative stress in cells [209]. So, CsA has been and remains a fantastic tool to decorticate the biochemical mechanism of PTP and provided new light on the sequence of events leading to ischemia–reperfusion injury. Its clinical use is difficult to consider in this indication but the search for more selective derivatives is probably the subject of intensive work.

3.4.2. Coenzymes Q Besides its antioxidant effects and its role in the regulation of electron transfer, a new property of the coenzyme Q family was recently provided by Bernardi’s group. They demonstrated that exogenous coenzyme Q 0 (ubiquinone 0) and decylubiquinone were very potent inhibitors of PTP opening induced by Ca 21 overload whereas coenzyme Q 1 (ubiquinone 5), which did not inhibit pore opening per se, counteracted the effects of coenzyme Q 0 and decylubiquinone [210,211]. In addition, like CsA these compounds inhibit PTP whatever the PTP inducer used (phosphate, membrane depolarization, atractylate or oxidative stress). They concluded that a specific quinone binding site modulate PTP opening. Whether this property takes part in the antiischemic

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effect of coenzyme Q remains, to our knowledge, unexplored but these findings may open a new field of investigation to design a novel structural chemical class of pore inhibitors.

3.4.3. Other pharmacological inhibitors Numerous drugs were found to inhibit PTP in vitro [212]. Most of these drugs are amphiphilic cations which are known to interact with biological membranes and could change mitochondrial potential which has also been proposed to explain the closure of the pore [207]. Indeed cationic compounds such as sphingosine [207], spermine [213] and divalent cations [214], which are believed to render the membrane potential more positive, inhibit pore opening. This hypothesis may be applied to trimetazidine which is a divalent cation and could perhaps modify the surface potential. It is interesting to note that we recently described the presence of specific binding sites for [ 3 H]trimetazidine on liver mitochondrial membranes which may be involved in the regulation of the mitochondrial permeability transition pore [212,215]. Generally, these effect were observed at high concentrations incompatible with their therapeutic concentrations. Few drugs escape this general rule. Amiodarone [216], trifluoperazine [217] and cinnarizine [218] act in the micromolar range and this effect can be expected to participate to their antiischemic effect.

4. Metabolic diseases, ischaemia and stress: interactions with mitochondria Glutamate is produced via oxidative metabolism via the Krebs cycle (Fig. 4) and GABA is also a substrate for the Krebs cycle yielding up to 17% of neuronal energy requirements in some instances. Lactate is produced from astrocytes as a local energy source from neurones. Thus ischaemia will markedly change brain function in that the metabolism of the main excitatory and inhibitory neurotransmitters will be disrupted. Mitochondria are critical in neurodegenerative diseases [219]. Thus it will be interesting to see if the compounds reviewed in this chapter

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which are shown to have acute effects in ischaemic models have effects in neurodegenerative diseases.

5. The particular case of the preserving solutions for organ transplantation Transplantation is a particular aspect of ischemia reperfusion injury with an uncommon kind of inflammation. Delayed graft function is clearly associated with poor allograft function, and is caused by an interaction of ischemic and immunological factors. In addition, delayed graft function complicates postoperative patient management. Many factors may contribute to the development of ischemia injury. The most important are the donor related factors (hypotension and bread-death related phenomena), cold ischemia (duration and method of storage), reperfusion injury, and the recipient factors. Preservation solutions have been designed to minimize ischemic damage during storage. Components are added to decrease cell swelling, maintain calcium homeostasis, decrease free radical substrate formation and provide high energy substrates [220]. These goals are fulfilled by drugs which preserve and maintain mitochondrial functions, i.e. oxidative phosphorylation, Ca 21 homeostasis and the limitation of ROS generation. Trimetazidine is a good example of such a drug (see Section 3.1.1.1.). It has been used to protect myocardium, liver, kidney and small bowel from ischemia–reperfusion injury [221– 224]. This drug was also efficient against cold ischemia. Trimetazidine was shown to improve the preservation of arrested rat hearts [225] and of pig kidneys exposed to cold ischemia [226]. Interestingly, we have recently demonstrated that the limitation of ischemia reperfusion injury by trimetazidine was also efficient against inflammatory cell infiltration [227]. This drug acts mainly at the renal medulla level which is extremely susceptible to injury in reducing ischaemia–reperfusion injury [228]. Ranolazine (see Section 3.1.1.2.) has also demonstrated a beneficial effect in a porcine model of renal autotransplantation [229] but these authors have probably renounced to use this drug in cold ischemia since, to our knowledge, any study had confirmed these results.

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Fig. 4. Mitochondria, stress and ischemia. AMPA R, a-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid receptor; NMDA R, Nmethyl-D-aspartate receptor; GAD, glutamic acid decarboxylase.

6. Conclusions This brief review reveals that during the past 10 years numerous drugs have been shown to modulate mitochondrial functions but none of them displays enough selectivity to assume the name of ‘mitochondrial antiischemic drug’. Mitochondria contain a lot of enzymes, channels and exchangers which

regulate the cellular metabolism. They represent potential targets for drugs but the role of the organite in the cell is so crucial that the drug effect must be specific and moderate. Such a drug is difficult to develop but the increasing number of works analyzing the interaction between drugs and mitochondria probably mean that a ‘mitochondrial drug’ exists in the near future.

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