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the antinociception induced by cold water swimming. Regul. Pept. 59, 255–259 Dubner, R. and Ren, K. (1999) Assessing transient and persistent pain in animals. In Textbook of Pain (Wall, P.D. and Melzack, R., eds), pp. 359–369, Churchill Livingstone Porro, C.A. et al. (1991) Central β-endorphin system involvement in the reaction to acute tonic pain. Exp. Brain Res. 83, 549–554 Zangen, A. et al. (1998) Nociceptive stimulus induces release of endogenous β-endorphin in the rat brain. Neuroscience 85, 659–662 Wu, H. et al. (2001) Antisera against endogenous opioids increase the nocifensive response to formalin:demonstration of inhibitory β-endorphinergic control. Eur. J. Pharmacol. 421, 39–43 Hamba, M. (1988) Effects of lesion and stimulation of rats hypothalamic arcuate nucleus on the pain system. Brain Res. Bull. 21, 757–763

59 Tseng, L.F. and Collins, K.A. (1996) Pretreatment with pertussis toxin differentially modulates morphine- and β-endorphin-induced antinociception in the mouse. J. Pharmacol. Exp. Ther. 279, 39–46

60 Mizoguchi, H. et al. (1996) Pretreatment with pertussis toxin spinally but not supraspinally attenuates cold water swimming-induced antinociception in the mouse. Eur. J. Pharmacol. 309, 37–40

Chemical names DSP4: N-(2-chloroethyl)-N-ethyl2-bromobenzylamine hydrochloride ICI171864: N,N-diallyl-Tyr-Aib-Aib-Phe-Leu L364718 (devazepide): 1-methyl-3-(2-indoloyl)amino5-phenyl-3H-1,4-benzodiazepine-2-one L365260: 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5phenyl-1H-1,4-benzodiazepin-3-yl)-N ′-(3-methylphenyl)urea PD135158: 4-{[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2[[[1.7.7-trimethyl-bicylclo[2.2.2]hept-2-yloxy]carbonyl] amino]propyl]amino]-1 phenylethyl]amino-4-oxo[1S-1α.2β[S*(S*)]4α]}-butanoate N-methyl-D-glucamine

SR95531: 2-(3-carboxypropy)-3-amino-6(4-methoxyphenyl)pyridazinium bromide (-)TAN67: 2-methyl-4aα-(3-hydroxyphenyl)1,2,3,4,4a,5,12,12aα-octahydro-quinolino[2,3,3g]isoquinoline U50488H: trans(±)-3,4-dichloro-N-methyl-N-[2-(1pyrrolidinyl)cyclohexyl]benzene-acetamide methane sulfonate WIN44441: (−)-1-cyclopentyl-5-(1,2,3,4,5,6hexahydro-8-hydroxy-3,6,11-trimethyl-2,6,methano3-benzazocine-11-yl)-3-pentanone methanesulfonoate

Cerebrovascular structure and dementia: new drug targets Jeffrey Atkinson Effective pharmacological treatment of cognitive disorders in dementia is lacking despite extensive efforts to produce active therapy aimed at neuronal and vascular targets. In this review, the evidence for the involvement of vascular mechanisms in the pathology and evolution of dementia will be examined and the potential importance of age-related changes in cerebrovascular structure and cerebral blood flow (CBF) autoregulation will be discussed. With a description of recent clinical results (on statins, angiotensinconverting enzyme inhibitors and Ca2++ channel blockers) and experimental results (on β-amyloid), the impact of drugs on cerebrovascular targets is examined. The working hypothesis that targeting vascular mechanisms in dementia is an option for future therapy is proposed.

Jeffrey Atkinson Cardiovascular Research Group Nancy (EA 3116), Pharmacy Faculty, Henri Poincaré University, 54000 Nancy, France. e-mail: atkinson@ pharma.u-nancy.fr

Recent reviews have discussed, in detail, the involvement of the vasculature in the pathology and evolution of dementia1–4. Briefly, the classification of dementia into primary, non-vascular [e.g. dementia associated with Alzheimer’s disease (AD)], and secondary, vascular (i.e. a wide range of dementias that have a primary vascular origin, such as cognitive decline associated with stroke, multi-infarct or cerebrovascular dementia, and white matter complications such as leukoaraiosis (neuroimaging abnormalities of the white matter encompassing a variety of pathological phenomena with different risk factors and forms of cognitive disturbance)] is changing. Indeed, evidence from experiments in humans and animal models suggests that the distinction between the two types of dementia might not be so clear-cut. For example, AD was found more often and was more severe in nuns who exhibited http://tips.trends.com

evidence of brain infarcts following cerebrovascular disease (CVD)5 than those nuns with no brain infarcts, which suggests that CVD precipitates AD at a stage when it would not be detected clinically. Leukoaraiosis is associated with a deficit in cognition6 whereas stroke survivors have a higher risk or intensity of dementia than stroke-free subjects7, and there is debate on the importance of silent strokes in dementia8. Silent strokes are a form of focal brain injury following blockage or rupture of a blood vessel that occurs without acute symptoms but that might be associated with mood disorder, memory loss and difficulty in walking. Events that are not primarily cerebrovascular in origin are also involved in the development of dementia. For example, coronary artery bypass surgery can produce long-term cognitive decline in ~50% of patients9, although the mechanism involved and the type of neuroprotective agent required to prevent such dementia are still under discussion. In old rats, chronic brain hypoperfusion produces deficits in visuo-spatial learning10, and the concept is emerging that the link between CVD and dementia reflects an amplification of progressive, age-related alterations in the regulation of cerebral blood flow (CBF)11. Cognitive function declines with age12 and mild cognitive impairment in an elderly individual might well represent early-stage AD with steady progression to greater stages of dementia severity13.

0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0165-6147(00)01866-6

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Fig.1. Short-term control of cerebral blood flow (CBF) is achieved by two mechanisms – autoregulation and metabolism. Direct neurohormonal control of vasomotion is minor compared with responses to metabolic and mechanical stimuli. (a) Over an input mean pressure range of 60–160 mmHg, blood flow is relatively independent of pressure because cerebrovascular resistance adapts to maintain flow. Abrupt changes in pressure are accompanied by transient changes in CBF in the same direction, but in a few seconds CBF returns to normal following vasodilatation with an initial fall in pressure, or vasoconstriction with an initial increase in pressure. Beyond the lower limit of the autoregulatory plateau, CBF falls along with pressure. The mechanisms that underlie autoregulation are not clearly understood and the following have been proposed: a myogenic response, vasoactive metabolites (CO2, H+, O2, K+, Ca2+ and adenosine) and, more recently, endothelial factors. (b) With respect to the metabolic control of CBF, hypercapnia (high concentrations of CO2 in the blood) increases CBF whereas hypocapnia (low concentrations of CO2 in the blood) decreases CBF. The major mechanism involved is changes in [H+] in the extracellular fluid: acidosis causes vasodilatation and alkalosis causes vasoconstriction. (c) Isocapnic hypoxia caused by hypoxaemia (e.g. altitude) or poisoning (e.g. cyanide) increases CBF. Local mechanisms (opening of ATP-dependent K+ channels or release of nitric oxide) and neurogenic mechanisms have been postulated to be involved in this process (for details see Ref. 49).

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The regulation of CBF is achieved by two mechanisms, autoregulation and metabolism (Fig. 1), that maintain tight control over flow. Such control is essential because the brain, which weighs 2% of body weight, consumes 20% of available oxygen and has no reserves of oxygen or glucose, making it very susceptible to ischaemia. Although it is possible that changes in baseline CBF with age occur in specific brain areas and involve certain, susceptible (genetic risk factors) subjects, the main changes that occur with age concern regulatory mechanisms (e.g. autoregulation14,15) rather than baseline flow. A similar phenomenon occurs in other vascular beds such as the coronary circulation16. One such change is a shift in the lower limit of autoregulation to a higher input mean pressure level (Fig. 2). Systolic arterial pressure rises progressively with age but diastolic pressure flattens and might actually fall over 50 years of age17. Thus, mean blood pressure – on which CBF autoregulation depends – probably does not increase in the elderly (who suffer mainly from isolated systolic hypertension). As the lower limit of CBF autoregulation is shifted to a higher pressure level, the security margin decreases. This, together with a greater blood pressure variability, produces a greater risk of periodic hypoperfusion and hence cerebral ischaemia. Insight into the way in which the lower limit of CBF autoregulation shifts is provided by the work of Baumbach and co-workers18, who found that the distensibility of the cerebral arteriole is reduced in aged rats and that the wall undergoes atrophy with age. Such changes are mainly due to a reduction in smooth muscle, which might result from an intrinsic change in smooth muscle lifespan or its ability to replicate. A decrease in an external trophic element such as sympathetic innervation might also contribute to these changes. As the arteriolar wall becomes stiffer, vasodilatory capacity can decrease, thus shifting the lower limit of CBF autoregulation (Fig. 3). Thus, a case can be made for the use of drugs that counteract the age-linked changes in the structure (geometry and composition) of cerebral arterioles in the treatment of dementia. Cerebrovascular structure: potential drug targets

The use of drugs that act at vascular targets to treat dementia is not new and dates back to the 1950s when several so-called ‘cerebral vasodilators’ were proposed. Drugs with a potential or proven cerebrovascular effect include those acting via receptors, such as α-adrenoceptor antagonists (e.g. ergot derivatives and others) and cholinergic drugs (e.g. muscarinic receptor agonists and acetylcholine releasers), or ion channels (e.g. Ca2+ channel antagonists such as nimodipine). A variety of drugs, such as papaverine, gingko derivatives and nootropic agents (cognition-enhancing drugs such as pentifylline and piracetam), act by mechanisms that are less well known. It was claimed that such agents would increase CBF and so improve

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Fig. 2. Compared with young people (a), the elderly (b) exhibit a shift in the lower limit of cerebral blood flow (CBF) autoregulation, which reduces the security margin – that is the extent to which mean blood pressure can fall before attaining the lower autoregulatory limit, producing a decrease in CBF and thus cerebral hypoperfusion. Because blood pressure varies widely over a given 24-h period, the risk of cerebral hypoperfusion is always present. Such a risk will be higher in the elderly given that the reduction in the autoregulatory security margin is accompanied by an increase in blood pressure variability50. (c) Such chronic, periodic cerebral hypoperfusion might be an essential element of the CATCH (critically attained threshold of cerebral hypoperfusion) phenomenon51. According to this hypothesis a multitude of vascular risk factors together with age induce CATCH, and chronic cerebral hypoperfusion leads to changes in capillary permeability and ischaemia with, ultimately, neuronal death leading to dementia.

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the supply of nutrients to neurones. However, definitive evidence of such a mechanism or of their clinical efficacy is scarce. Thus, these drugs are often used (to the possible detriment of the use of more adequate therapy) but might not be very beneficial, although the use of such compounds is declining rapidly, even in France, a country in which they were once widely used19. It is generally hypothesized that these drugs are functional vasodilators and are involved in the short-term control of CBF. Given the tight metabolic and autoregulatory control over CBF, the effects produced by these drugs would be expected to be counteracted immediately, which would explain their long-term inefficacy. http://tips.trends.com

The reactions of blood vessels to different agents can be classified broadly into ‘immediate’ (e.g. vasomotion and capillary hydromineral exchange, among others) and ‘late’ (e.g. trophic effects on wall thickness, wall remodelling and changes in blood–brain barrier permeability). Several drugs that affect cerebrovascular structure have exhibited [e.g. statins, angiotensin-converting enzyme (ACE) inhibitors and Ca2+ channel blockers] or are suggested to possess (e.g. factors counteracting amyloid angiopathy) a protective effect in dementia. Statins

Using the General Practice Research Database, which covers >3 million residents in the UK, it was found that in subjects who were >50 years old, those prescribed statins (3-hydroxy-3-methylglutaryl coenzyme A inhibitors) had a lowered risk of developing dementia than those who did not exhibit hyperlipidaemia or those who were not receiving lipid-lowering agents20. The effect of statins was independent of the presence of hyperlipidaemia or the use of non-statin lipid-lowering agents. When considering the effect of statins on cerebrovascular structure there is evidence both for and against a beneficial impact. Lovastatin lowers intracellular cholesterol and thus inhibits β-secretase cleavage of the transmembrane amyloid precursor protein [the product of which (β-amyloid) is deposited as senile plaques in AD]21. Inhibition by statins of such β-amyloid-induced vascular wall degeneration (see below) would protect wall integrity and flow regulatory mechanisms. However, the pharmacology of statins is complex and statins have also been shown to inhibit isoprenoid synthesis and prenylation of key intracellular proliferation proteins such as members of the Ras and Rho families of monomeric G proteins22. This effect would reduce the thickness of the arteriolar wall. We have recently shown that treatment of young spontaneously hypertensive (SHR) rats with lovastatin for one month reduces the cross-sectional area of the arteriolar wall and increases wall stiffness23. Although experiments in old animals have not been performed, a similar effect in the elderly would not be beneficial for the cerebral circulation. Thus, the case for statins is open but, given their widespread use and the clinical importance of a beneficial effect on dementia, further experiments on their impact on cerebrovascular structure is required. ACE inhibitors

Recent results on the impact of the ACE inhibitor perindopril on cognitive performance show that ACE inhibitors have a beneficial effect on the development and management of dementia (PROGRESS study24). As in the case of statins, experiments using ACE inhibitors have been performed in young rat models but rarely in old animals. In young hypertensive rats, perindopril

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β-Amyloid and other factors

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Fig. 3. In old, normotensive rats arteriolar internal diameter does not change and because mean arterial pressure does not increase with age, baseline cerebrovascular resistance and hence flow do not change with age. However, thinning and stiffening of the wall of the cerebral arteriole with age might hinder the extent to which arterioles can dilate (or constrict) following changes in input perfusion pressure. A stiffer wall might have a lower vasomotor capacity per se but this will be a difficult mechanism to verify in vivo. The wall might become stiffer with age because it loses a distensible component (smooth muscle) at the expense of a less distensible component (collagen)18. The loss of smooth muscle would also lead to lower arteriolar contractility, so changes in contractility and stiffness might evolve concomitantly but not be causally linked. Although the above mechanism is relatively well described in animal models, for obvious ethical reasons evidence for its existence in humans is lacking. Periodic hypoperfusion resulting from changes in arteriolar structure and function might also be, at least partially, responsible for downstream ischaemia at the capillary level, a risk that is increased by the increased variability in blood pressure over a given 24-h period with age. Farkas and colleagues11,52 have suggested that ischaemia-induced cerebral microvascular pathology provides the link between aging, hypertension and Alzheimer’s disease. β-Amyloid is a heterogeneous 39–42-amino-acid peptide that is a major component of senile plaques and cerebrovascular deposits. Its cytotoxicity plays a major role in the pathophysiology of dementia.

attenuates hypertension-induced wall remodelling (possibly in a pressure-independent fashion) and improves cerebrovascular dilatory reserve25,26. Although experiments on arteriolar structure and function in old animals are lacking, similar beneficial effects might well occur in older animals because treatment with perindopril shifts the lower limit of cerebral blood flow autoregulation to a lower pressure level in old, normotensive rats27. Ca2+ channel blockers

In the Systolic Hypertension in Europe trial, elderly patients who possessed systolic hypertension and were treated with antihypertensive drugs (the Ca2+ channel blocker nitrendipine, with possible addition of enalapril and/or hydrochlorothiazide) exhibited a http://tips.trends.com

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lower incidence of dementia compared with similar patients treated with placebo28. The authors suggested that this might be due to a specific neuronal effect of nitrendipine, although cerebrovascular effects might also be involved. Chronic treatment with Ca2+ channel blockers has been shown to shift CBF autoregulation to a lower pressure level in young SHR rats29 and to preserve capillary integrity in aging stroke-prone spontaneously hypertensive (SHR-SP) rats30. In the latter study of SHP-SR rats, the authors suggested that the Ca2+ channel blocker nimodipine, which in their experiments did not lower blood pressure, might moderate free radical production and consequent capillary injury. Thus, a link might exist between dementia and the inflammatory reaction involved in amyloid angiopathy (see below). With both ACE inhibitors and Ca2+ channel blockers, difficulties of interpretation of the data arise when considering the effects of antihypertensive drugs because prior hypertension is one of the risk factors for the development of dementia31. However, results using other drugs have not shown a beneficial effect. For example, the Systolic Hypertension in the Elderly Program (SHEP) did not show that antihypertensive treatment with the thiazide-like diuretic chlortalidone would reduce dementia, although it has been claimed that problems such as selective dropout might have obscured the recognition of treatment benefit32. Furthermore, a UK trial showed that treating moderate hypertension with a diuretic or a β-blocker did not influence cognition33. Given the clinical importance of this issue, more work is needed on: (1) which drugs, used primarily for systemic vascular disorders, have a pressureindependent, cerebrovascular protective effect; and (2) the structural and functional bases of this effect and its relevance to dementia. β-Amyloid

Amyloid angiopathy consists of deposition of β-amyloid in cerebral blood vessels, which destroys wall integrity (Fig. 4) and might be one of the primary factors involved in the age-related changes in the cerebral microvasculature outlined above (Fig. 3). Indeed, there is intensive effort in the pharmacotherapy of β-amyloid toxicity34,35. There are two major approaches: conventional pharmacotherapy aimed at transduction pathways and enzymes involved in the formation of β-amyloid, and direct targeting of β-amyloid by β-sheet breakers and other strategies. Other drugs that were not primarily designed as anti-amyloid agents might also interfere with these processes36. Because β-amyloid might mediate its toxicity via an inflammatory reaction (Fig. 4), anti-inflammatory drugs could be useful; such drugs might act by binding to the transcription factor peroxisome proliferator activated receptor γ (PPAR-γ) rather than by inhibition of cyclooxygenase (COX)37. β-Amyloid reduces the production of nitric oxide (NO)

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Circulating β-amyloid Local production of β-amyloid Increased cleavage of β-amyloid precursor protein

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Fig. 4. Evidence is being acquired that β-amyloid circulates in the blood53,54 or in platelets55,56 and can fix onto RAGE (receptor for advanced glycation end products)57,58 . This induces an oxidative, inflammatory reaction involving an increase in the concentration of intracellular Ca2+ (Refs 59,60). Several cell types could be involved. Vasoconstriction following stimulation of smooth muscle cells61,62 could lead to cerebral hypoperfusion. Monocyte activation58 could lead to wall cell loss63,64 producing decreased flow autoregulation, as described previously, and thus cerebral hypoperfusion. Decreased fluidity following changes in red blood cells65 could also lead to cerebral hypoperfusion. A fourth cellular target is the endothelial cell, in which damage possibly involving apoptosis66 could lead to increased permeability of the blood–brain barrier67,68 . Finally, this process might involve positive feedback mechanisms; for example, it is known that cerebral hypoperfusion increases cleavage of β-amyloid precursor protein69.

and so drugs that increase the production of NO might also be useful in reducing β-amyloid toxicity38. Furthermore, reduced endothelial nitric oxide synthase (eNOS) expression in cerebral vessels is associated with vascular lesions and amyloidosis (infiltration of the liver, kidneys, spleen and other tissues with amyloid)39. It has been suggested that drugs such as the monoamine oxidase B inhibitor L-deprenyl increase NO production and block β-amyloid-induced contraction in bovine middle artery vessels (by an unknown mechanism) and thus protect against the toxic effects of β-amyloid40. In addition, K+ channel openers might protect cells because the References 1 Kalaria, R.N. (2000) The role of cerebral ischemia in Alzheimer’s disease. Neurobiol. Aging 21, 321–330 2 Kudo, T. et al. (2000) Are cerebrovascular factors involved in Alzheimer’s disease? Neurobiol. Aging 21, 215–224 3 Shi, J. et al. (2000) Vascular abnormalities: the insidious pathogenesis of Alzheimer’s disease. Neurobiol. Aging 21, 357–361 http://tips.trends.com

ATP-dependent K+ channel opener diazoxide and the Ca2+-sensitive K+ channel opener NS1619 have been shown to counteract cytotoxicity and decrease NO production in bovine vascular endothelial cells41. The relationship between the two effects has not been elucidated but it has been suggested that oxygenderived free radicals such as superoxide are involved41. Drugs that act on Ca2+ channels have also been proposed42,43; indeed, cellular damage and death produced by β-amyloid25–35 is attenuated by the Ca2+ channel blocker nimodipine42. Other types of Ca2+ channel might be involved because it has been proposed that β-amyloid1–42 produces cellular degeneration by elevating the intracellular Ca2+ concentration most probably via a Ca2+-permeable β-amyloid channel43. Following on from observations that post-menopausal women treated with estrogen have a lower risk of AD, it has been suggested that estradiol might prevent β-amyloid accumulation by stimulating α-secretase44. A final example is provided by melatonin, which might be anti-amyloidogenic by virtue of its antioxidant properties45. The case of melatonin is interesting because we have recently shown that nanomolar concentrations of melatonin stimulate specific receptors on the arteriolar wall46 and improve the CBF security margin in rats47. Furthermore, following pinealectomy (removal of the pineal gland, which secretes melatonin) the cerebral arteriolar wall becomes thinner and stiffer, effects that can be reversed by giving the pinealectomized rats a melatonin solution to drink48. Concluding remarks

Cerebrovascular disease is of immense importance given the large number of people afflicted by this disorder and the fact that this number will increase in the future with the prolongation of life expectancy. Data relevant to the pathophysiology of cerebral ischaemia could offer an improved outlook in the treatment of AD. In this article, a case has been made for targeting vascular structure in the treatment of cognitive disorders. Recent evidence shows that drugs used for the treatment of systemic vascular disorders such as hypertension (e.g. ACE inhibitors or Ca2+ channel blockers) or hyperlipidaemia (e.g. statins) modify the evolution of dementia in humans and have effects on cerebrovascular structure and function in animals. Another new area for research is provided by modulation of the oxidative, inflammatory process that accompanies the progression of cerebral amyloid angiopathy.

4 Stewart, R. (1998) Cardiovascular factors in Alzheimer’s disease. Editorial. J. Neurol. Neurosurg. Psych. 65, 143–147 5 Snowdon, D.A. et al. (1997) Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. J. Am. Med. Assoc. 277, 813–817 6 Pantoni, L. and Garcia, J.H. (1995) The significance of cerebral white matter abnormalities 100 years after Binswanger’s report. A review. Stroke 26, 1293–1301

7 Prencipe, M. et al. (1997) Stroke, disability and dementia: results of a population survey. Stroke 28, 531–536 8 Leys, D. et al. (1999) Vascular dementia: the role of cerebral infarcts. Alzheimer Dis. Assoc. Disord. 13, S38–S48 9 Newman, M.F. et al. (2001) Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. New Engl. J. Med. 344, 395–402

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