Current insights into pathogenesis of Parkinson’s disease: Approach to mevalonate pathway and protective role of statins

Biomedicine & Pharmacotherapy 90 (2017) 724–730

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Review

Current insights into pathogenesis of Parkinson’s disease: Approach to mevalonate pathway and protective role of statins Seyed Soheil Saeedi Saravia,b,1 , Seyed Sobhan Saeedi Saravic,1 , Katayoun Khoshbind, Ahmad Reza Dehpourb,e,* a

Department of Toxicology-Pharmacology, Faculty of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Department of Toxicology-Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran d School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran e Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran b c

A R T I C L E I N F O

Article history: Received 16 January 2017 Received in revised form 7 April 2017 Accepted 10 April 2017 Keywords: Parkinson’s disease Neurodegeneration Mevalonate pathway Statins

A B S T R A C T

Although Parkinson’s disease (PD) is considered as the second most common life threatening age-related neurodegenerative disorder, but the underlying mechanisms for pathogenesis of PD are remained to be fully found. However, a complex relationship between genetic and environmental predisposing factors are involved in progression of PD. Dopaminergic neuronal cell death caused by mutations and accumulation of a-synuclein in Lewy bodies and neurites was suggested as the main strategy for PD, but current studies have paid attention to the role of mevalonate pathway in incidence of neurodegenerative diseases including PD. The discovery may change the therapeutic protocols from symptomatic treatment by dopamine precursors and agonists to neurodegenerative process halting drugs. Moreover, the downstream metabolites of mevalonate pathway may be used as diagnostic biomarkers for early diagnosis of PD. Statins, as cholesterol lowering drugs, may ameliorate the enzyme complex dysfunction, a key step in the progression of the neurodegenerative disorders, oxidative stress-induced damage and neuro-inflammation. Statins exert the neuroprotective effects on striatal dopaminergic neurons through blocking the mevalonate pathway. In the present review, we have focused on the new approaches to pathogenesis of PD regarding to mevalonate pathway, in addition to the previous understood mechanisms for the disease. It tries to elucidate the novel findings about PD for the development of future diagnostic and therapeutic strategies. Moreover, we explain the controversial role of statins in improvement or progression of PD and the position of these drugs in neuroprotection in PD patients. © 2017 Published by Elsevier Masson SAS.

Contents 1. 2. 3. 4.

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Introduction . . . . . . . . . . . . . . . . . . . . . . Pathogenesis of Parkinson’s disease . . . New approaches to pathogenesis of PD Role of statins in PD . . . . . . . . . . . . . . . . Statins . . . . . . . . . . . . . . . . . . . . . 4.1. Statins and PD . . . . . . . . . . . . . . . 4.2. Neuroprotective effects of statins 4.3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author at: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. E-mail address: [email protected] (A.R. Dehpour). 1 The first two authors are equally considered as leading author. http://dx.doi.org/10.1016/j.biopha.2017.04.038 0753-3322/© 2017 Published by Elsevier Masson SAS.

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1. Introduction Parkinson’s disease (PD), as a debilitating progressive neurodegenerative disorder, is the second most common age-related disease after Alzheimer disease [1,2]. This disease is spreading from 1% of world population over 50 years to 4% of those over 65 years [2–5]. In addition to age, incidence of the disease strongly depends on sex, genetic, ethnical and geographical factors. However, combination of a specific genetic background with a predisposing life style elevates two- to seven-fold the risk of incidence of PD [6]. PD is classified as the life-threatening diseases that shorten the duration of life, as mortality among PD patients three times more frequent than general population. It is characterized by a tetrad of permanently progressing clinical traits, bradykinesia, resting tremor, muscle rigidity, postural instability, following impaired motor function [6–8]. The patients with PD manifest both motor and nonmotor symptoms (NMS), including depression, autonomic dysfunction, sleep disturbances, sensory abnormalities, and cognitive decline [9]. The impairment of dopaminergic system following depigmentation of substantia nigra (SN) and cytoplasmic Lewy bodies (LB) are considered as the main reason for PD. Although the pathophysiological causes of motor dysfunction in PD have been well understood, the underlying mechanisms of NMS are not fully found [10–12]. As a result, there is an open avenue for the research on predisposing and possible mechanisms of pathogenesis of PD. The findings will facilitate the discovery of new therapeutic strategies for PD. Moreover, the controversial role of statins in improvement or progression of PD is discussed for clarification of their position in neuroprotective process. 2. Pathogenesis of Parkinson’s disease As a neurodegenerative disease, PD is correlated to the selective death of different types of neurons. At first step, loss of dopaminergic neurons located in the substantia nigra pars compacta (SNc) of basal nuclei, and in the tectum mesencephalicum is observed [2,6,13–15]. The decreased level of dopamine in the putamen and in the corpus striatum followed by neuronal cell death in substantia nigra leads to the emergence of motor symptoms. Clinical studies have demonstrated that typical clinical signs of PD are displayed in accordance to the death of 60–80% of dopaminergic neurons of substantia nigra pars compacta, as well as, an 80% of decrease in dopamine level in the putamen [6,14,15]. In PD, Lewy bodies and Lewy neurites, composed by proteins, fats, and polysaccharides, with radiating filaments, including a-synuclein, neurofilaments, ubiquitin, parkin, and synphilinin, aggregate in the substantia innominata [13,16]. In one hand, Lewy bodies play a neuroprotective role in PD and some other neurodegenerative diseases such as multiple systemic atrophy and Alzheimer’s disease, and in healthy elderly persons [17]. On the other hand, aggregation of Lewy bodies in substantia nigra contributes to neuronal death in PD. Other features of the neurodegenerative modifications in this disease are the development of gliosis in corpus striatum and substantia nigra, leading to activation of microglia [6]. Moreover, some other potential predisposing factors contributes to pathophysiology of PD. Oxidative stress and alteration of mitochondrial function are associated with loss of dopaminergic neurons, which is caused by MPP+ (1-methyl-4-phenylpyridinium), a metabolite of mitochondrial permeability transition pore (MPTP). Disrupted catabolism of unwanted impaired or mutated multiple proteins in Lewy bodies and neurites, most notably a-synuclein, leads to cellular aggregation and neuronal death [2,18–21]. Alterations in the proinflammatory cytokines, including interleukin-1a (IL-1a), IL-1b and tumor necrosis factor-a (TNF-a), and inducible nitric oxide

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synthase (iNOS) in activated microglia are appeared. Moreover, excitotoxicity is involved in neuronal cell death caused by PD [2,22]. Although microglia activation and inflammatory response changes were both thought to be the major causes of neuronal disruption, there is body of evidences that general systemic inflammatory reactions are contributed to the pathogenesis of PD. Regarding to the widespread neuropathological picture of PD, it is assumed that degenerative processes can also be occurred in many nondopaminergic nuclei, including locus coeruleus, reticular formation of the brain stem, pedunculopontine nucleus, raphe nucleus, dorsal motor nucleus of the vagal nerve, olfactory bulbs, parasympathetic and sympathetic postganglionic neurons, basal Meynert nucleus, amygdala, hippocampus, and cerebral cortex. Degeneration of these structures by Lewy bodies leads to incidence of nonmotor clinical symptoms [23]. Furthermore, motor and nonmotor symptoms of PD are manifested, step by step, following pathological changes in dorsal motor neurons of vagal nerve, medulla oblongata, tectum mesencephalicum, and olfactory apparatus. These are resulted in olfactory disorders, constipation and sleep disturbances [24]. The typical signs of PD are developed since the dopamine level is decreased in putamen and corpus striatum, following substantia nigra and limbic system neuronal death. Ultimately, involvement of neocortex leads to loss of memory and cognitive disorders [25,26]. Despite the quoted neuropathological causes of PD, the putative role of genetic factors in the pathogenesis of PD has long been discussed. Epigenetic modifications, environmental factors and genetic mutations participate as vital players in development and regeneration of the disease [27]. Investigation of effective genetic factors on pathogenesis of PD revealed that mutations in at least 17 autosomal dominant and autosomal recessive genes are underlying the variants of the disease [28]. These gene mutations are found in a-synuclein (triplication), Parkin, ubiquitin carboxyl- terminal hydrolase L1 (UCH-L1), Parkinson disease protein 7 (DJ-1), phosphatase and tensin homolog-inducible kinase1 (PINK1), leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) [2]. According to the poorly known role of Lewy bodies in pathogenesis of PD, researchers have discovered an important role for a-synuclein, a major component of the radiating filaments. They mentioned that accumulation of a-synuclein protein in Lewy bodies and Lewy neurites is a pathologic hallmark of PD. As a result, dominant mutations in the a-synuclein gene (SNCA) are implicated as a distinct underlying mechanism for neurodegenerative events of PD [4,29–31]. 3. New approaches to pathogenesis of PD In the past 2 decades, brilliant advances have been obtained in finding out the mechanistic perspective of PD. Although none of current therapeutic protocols for PD have proved to obtain a convincing effect on the motor symptoms [32–36], but progressing investigations of new therapeutic strategies are performed to stop or to slow the development rate of the disease. Currently, mevalonic acid, the substrate for cholesterol and isoprenoid ubiquinone production, is located in the center stage of studies to find the pathogenic factors associated with Parkinson's disease. This phenomenon was first introduced in 1995, when Muller et al. implied a link between treatment with lovastatin, a 3-hydroxy-3methylglutaryl Co-enzyme A (HMG-CoA) reductase (HMGCR) inhibitor, and PD in two patients [37]. They demonstrated that an inborn error of mevalonate kinase results in decreased synthesis of cholesterol and coenzyme-Q10 (Co-Q10) and, in overall, a neurological disorder [37,38]. An impairment of cholesterol synthesis is suggested to be involved in PD [39]. On the other hand, Investigations have suggested a neuroprotective effect for

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statins in several neurodegenerative disorders such as stroke, Alzheimer's disease and PD. These reports showed that statins attenuate a-synuclein aggregation in transfected neurons [40–42], while some other studies have indicated that statins exert their neuroprotective effects via a variety of mechanisms including lowering cholesterol, anti-inflammatory responses, anti-thrombotic effects, suppression of intracellular adhesion molecule-1 (ICAM-1), reduction of serum levels of apolipoprotein E, modification of cognition related receptors, and augmentation of endothelial nitric oxide synthase (eNOS) along with an increase in cerebral perfusion [41–44]. The most important neuroprotective mechanism of statins may be amelioration the enzyme complex dysfunction (decreased complex-I and III activity), a key step in progression of the neurodegenerative disorders. Also, oxidative stress-induced damages (lipid peroxidation, nitrite concentration and depleted glutathione peroxidase activity) and neuro-inflammation (enhanced TNF-a and IL-6 levels) are augmented by statins. Neuro-inflammation is well associated with infiltration of inflammatory cells into CNS [41,45–47]. Therefore, mevalonate can reverse the inhibition of T-cells mediated by statins [48]. Contrary to statins, mevalonate can reduce leukocyte infiltration, the surface expression of chemokine receptors on leukocytes, and additionally the circulating chemokines levels [49,50]. It is observed that mevalonate-dependent manner of statins include down-regulation of NADPH oxidase (Nox1) mRNA expression, inhibition of Rac1 (ras-related C3 botulinum toxin substrate 1) membrane translocation and suppressing O2 generation. This exerts the neuroprotective action against oxidative stress [51,52]. Selley and Xu et al. emphasized their findings which notably indicate the ability of simvastatin to completely reverse the impaired striatal dopamine activity and the synthesis of nitrosylated free radicals [42,51,53]. They established the role of simvastatin in preventing striatal dopamine depletion through a reduction in release of proinflammatory mediators from microglia. This is obtained through blocking the mevalonate pathway. Moreover, excessive mevalonate-induced typical neurodegenration in Mevalonate Kinase Deficiency (MKD), the second enzyme of the mevalonate pathway, is linked to both intrinsic apoptosis pathway (caspase-3 and 9), which is triggered by mitochondrial damage, and pyroptosis (caspase-1) combined with neuro-inflammation. This leads to impaired production of neuronal-supporting and anti-inflammatory molecules such as TGF-b and IL-10, and to activation of IL-1b, most important pro-inflammatory cytokine [54–56]. In addition, mitochondrial dysfunction with releasing ROS and other oxidative molecules is concluded as a center point of neurodegenerative disorders caused by mevalonate accumulation. The role of mevalonate pathway in the pathogenesis of neurodegenerative diseases is crucial and controversial. Since, Lim et al. has reported that lanosterol, the downstream metabolite of mevalonate, may cause mitochondrial uncoupling, resulting in neuroprotective effects by reducing superoxide species [57–59]. In addition to statins, peroxisome proliferator-activated receptoralpha (PPAR-a) agonists influence on an interesting pharmacological target to prevent or to slow the development of PD. There is body of evidences that PPAR-a is probably involved in inflammation and oxidative stress processes [60–68], as well as, suppression of apoptosis [69]. Mevalonate, as a component of an indirect pathway, enhances the sensitivity of PPAR-a to natural ligands, leading to its activation, and in turn, neuroprotection in PD [60,70]. 4. Role of statins in PD 4.1. Statins Statins are categorized into two classifications based on their origin: the fungus derived (e.g. lovastatin, simvastatin and

pravastatin) and the synthetic (e.g. atorvastatin, fluvastatin and rosuvastatin) drugs. Most of the intestinal tract-absorbed statins are taken up by liver, and the rest is systemic circulated in plasma proteins-bound form. In addition, liver, which cholesterol synthesis is located in, is the main target of these compounds. Statins are formulated in the two forms of active and prodrug, such as simvastatin and lovastatin, which are metabolized by liver to active drug [71–73]. The most common side effects of statins are summarized as gastrointestinal symptoms, myopathy, hepatotoxicity, peripheral neuropathy and skin rash [73]. Although animal experiments and clinical trials have demonstrated that lipophilic statins, simvastatin and lovastatin, have an ability to cross the blood–brain barrier [71,74,75], none of the reliable reports have shown a significant difference in the neuroprotective properties between lipophilic and lipophobic statins (Fig. 1). 4.2. Statins and PD In contrast to previous assumption that statins have not beneficial effects on Parkinson's disease, recent studies have indicated to the potential of these drugs to attenuate the motor or non-motor symptoms and to ameliorate the incidence and/or progression of PD [71,76,77]. Several studies have shown an association between low cholesterol level and development of PD [78]. Therefore, statins were believed to increase the risk of PD, due to their cellular cholesterol- and isoprenoid ubiquinone-lowering activity [76,77,79]. Conversely, neuronal cell cultures, as well as, animal investigations have implied that statins suppress a-synuclein aggregation [80–82]. These data were in line with clinical findings that statins attenuate a-synuclein deposition in the brain regions of PD patients through their cholesterol reduction properties [82,83]. The direct relationship between administration of statins and PD risk has been observed in a population-based case control study [85,86]. Statins administration is suggested to result in prevention of dopaminergic neuronal loss and improvement of behavioral deficits in animal models and clinical studies of PD [87– 89]. Epidemiological studies have also indicated to a reduced incidence of PD in long-term statin-users [84,90,91], while such meta-analyses emphasized that long-term statin use causes no significant risk reduction in PD patients [92]. A meta-analysis, using several clinical trials and observational studies, by Sheng et al. [92] have shown an obvious association between treatment with statins and decreased incidence of PD, especially in Asian population compared to western population, suggesting these drugs as an adjuvant therapy of PD patients. These data support the hypothesis that statins may exert neuroprotective effects in a cholesterol-independent pattern [71]. The literature concludes that cholesterol and statins play a controversial role in the neurodegenerative disorders. Despite of the reported association between high plasma cholesterol levels and lower incidence of PD [77,78,93], there is evidence of an increased risk of developing PD in patients with dyslipidemia (high levels of plasma cholesterol) [93]. It is notified that these are hydroxylated cholesterol derivatives, which are higher in the brains of PD patients compared to controls [93,94]. These derivatives, such as 27-hydroxycholesterol, increase the level and aggregation of a-synuclein and, eventually, decrease the synthesis of dopamine [93,95,96]. In contrast, cell culture and transgenic mouse model studies have specified the role of statins in reduction of a-synuclein aggregation [40,97]. Thus, it is supposed that statins might ameliorate the deposition of a-synuclein aggregates in the brain by lowering plasma cholesterol levels [93]. The limited experimental studies have determined some possible mechanisms for statin-induced neuroprotection in Parkinson’s disease. Statins may protect the dopaminergic neurons

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Fig. 1. A schematic model for current recognized and new contributed mechanisms underlying Parkinson's disease. ROS: reactive oxygen species, MPP+: 1-methyl-4phenylpyridinium, TNF-a: tumor necrosis factor-alpha, IL: interleukin, TGF-b: tumor growth factor-beta, eNOS: endothelial nitric oxide synthase, iNOS: inducible nitric oxide synthase, PPAR-a: Peroxisome proliferator-activated receptor-alpha, apo-E: apolipoprotein E, ICAM-1: intracellular adhesion molecule-1, Nox1: NADPH oxidase, Rac1: rasrelated C3 botulinum toxin substrate 1, UCH-L1: ubiquitin carboxyl- terminal hydrolase L1, DJ-1: Parkinson disease protein 7, PINK1: phosphatase and tensin homologinducible kinase1, LRRK2: leucine-rich repeat kinase 2, GBA: glucocerebrosidase.

of substantia nigra against neurodegeneration through inhibition of neuro-inflammatory responses [43,71]. For instance, simvastatin and pravastatin have been found to protect 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-treated mice, animal model of PD, through blocking the activation of iNOS, NF-kB, p21 (ras) and glial cells in the substantia nigra [81]. Simvastatin was shown to delay dopaminergic neuronal degeneration in lipopolysaccharideinduced PD rats, demonstrating the role of statins in the activation of brain-derived neurotrophic factor (BDNF) and inhibition of proinflammatory factors, IL-1b, TNF-a, iNOS, MAPK, and Akt [43]. Body of evidences has claimed that statins can ameliorate a-synuclein aggregation in the Lewy bodies, a pathophysiological feature of PD, in transfected neurons [40,42,54,55,71]. Some other studies have indicated that statins exert their neuroprotective

effects through a variety of mechanisms including reduction of oxidative stress-induced damage by inhibition of lipid peroxidation and nitrite concentration, of the depletion of mitochondrial enzyme complexes I, III and cytoprotective radical scavenging enzyme glutathione peroxidase, and of subsequent a-synuclein aggregation [42,45–47,98]. The neuro-inflammatory processes are also thought to be another target for statins. They are expected to exert neuroprotective effects by enhancing anti-inflammatory cytokines, such as TGF-b, rather than pro-inflammatory genes and cytokins [45–47,97]. On the other hand, statins are suggested to modulate dopamine receptors for prevention of PD progression. For example, studies using rat model of (6-OHDA)-induced PD demonstrated that long-term administration of high dose of simvastatin causes a significant up-regulation of dopamine D1/D2

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receptors in the brain [99,100]. However, more investigations are needed to clarify the exact mechanisms underlying the statininduced neuroprotection in PD patients. 4.3. Neuroprotective effects of statins Statins have been suggested to be neuroprotective drugs with anti-inflammatory, antioxidant, and anti-excitotoxicity. The foremost modes of the neuroprotection include: (1) modulation of the inflammatory responses; (2) reduction of oxidative stress-induced damage; (3) improvement of central blood flow by regulation of NO synthesis, anti-coagulation, and promotion of angiogenesis [71,101]. Some of neuroprotecive effects of statins, such as enhancement of resistance to excitotoxicity, are associated to a cholesterol-dependent manner through blocking HMGCR, which could be reversed by mevalonate or cholesterol treatment [71,102]. On the other hand, cholesterol-independent activity of statins plays crucial role in their neuroprotective effects. They stimulate neurogenesis and synaptogenesis after brain injury, and also promote the release and expression of neurotrophic factors such as BDNF. Furthermore, statins indirectly activate signaling cascade consisted of protein kinase B (PKB/Akt) and nuclear factor kappalight-chain-enhancer of activated B cells (NF-kB) by increasing TNF receptor 2 expression [103,104]. Along with the activation of PKB/ Akt, glycogen synthetase kinase-3 beta (GSK-3b), Rho-associated kinase (ROCK) and phosphatase and tensin homolog (PTEN), a negative regulator of PKB/Akt, are inhibited [105–107]. To our knowledge, another mechanism suggested for neuroprotective action of statins is activation of the Ras-ERK (extracellular-signalregulated kinase) signaling cascade [108]. 5. Conclusions Despite of the obvious progression in diagnosis of Parkinson’s disease, there are no distinct biomarkers for early diagnosis of PD. Thus, novel biomarkers are needed to be explored for early and reliably detection of retarded pathological progression. Reports have shown that the majority of present anti-parkinson agents (e.g. dopamine precursors and agonists) can only ameliorate the symptomatic effects, but are unable to halt the neurodegenerative processes, for instance, via blocking the mitochondrial damage and subsequent neuronal death. Otherwise, statins are pronounced as neuroprotetive drugs which can prevent the development of neurodegenerative diseases through different mechanisms. Whereas, none of the studies have fully elucidated the positive effect of blockade of mevalonate pathway on neurodegenerative disorder PD, the recent experiments are concentrated on the potential of statins for reduction of PD incidence. However, general neuroprotective effects of statins might not solely be related to blocking the mevalonate pathway and subsequent cholesterol synthesis. Therefore, further investigations are necessary to explain the main mechanisms underlying the neuroprotective effects of statins. Conflicts of interest The authors declare that there are no conflicts of interest. References [1] M. Ozansoy, A.N. Basak, The central theme of Parkinson's disease: alphasynuclein, Mol. Neurobiol. 47 (2013) 460–465. [2] D.T. Dexter, P. Jenner, Parkinson disease: from pathology to molecular disease mechanisms, Free Radic. Biol. Med. 62 (2013) 132–144. [3] Parkinson’s Disease and Parkinsonism Syndrome, in: V.L. Golubev, Y.I. Levin, A.M. Wein (Eds.), MED Press, Moscow, 2000.

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