A number of mechanisms have been implicated in statin-induced protection against cognitive impairment, including both cholesterol-dependent and -independent mechanisms. Increased LDL levels and total cholesterol have both been independently associated with cognitive impairment, thus the lowering of these lipoprotein levels, through statin treatment or other pharmacological/dietary means, has been suggested as a strategy for preventing cognitive impairment [52,53]. Despite this apparent disease link, statins have not only been implicated in cholesterol-associated reductions in cognitive impairment, but have also been found to reduce the odds of cognitive impairment independent of lipid levels [54].
perkins reaction mechanism pdf 15
Download: https://miimms.com/2vEihC
Although HMG-CoA reductase is the rate-limiting step of cholesterol biosynthesis in humans, it is only the second step of a 28-step process (see Figure 1). Consequently, statin treatment also prevents the production of a number of intermediary molecules, including isoprenoid products such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). It has been suggested that much of the cholesterol-independent actions of statins may be attributable to the inhibition of these isoprenoids, including effects on cognitive function. The inhibition of farnesylation by simvastatin has been associated with the enhancement of long-term potentiation between neurons in mice [55]. This study also found that the protective effect of statin treatment was abolished following replenishment of FPP, but not GGPP. Paradoxically, it has been suggested in other studies that the constant production of GGPP, but not FPP or cholesterol, is required for neurite outgrowth and maintenance, long-term potentiation and learning [56,57], possibly suggested differing neuroprotective effects associated with these two isoprenoid intermediates. Given the different roles each of these compounds has, known differences in FPP/GGPP ratios across various brain regions may subsequently result in different local statin-induced effects within these regions. The mechanisms underlying the differential distribution of FPP and GGPP across the brain, and the interplay this has with statin effect, are not known.
Another possible cellular mechanism which may underlie the possible beneficial cognitive effect of statins is the alteration of adult neurogenesis. It is hypothesized that suppression of adult neurogenesis may contribute to cognitive dysfunction and emotional symptoms in neurological and psychiatric disorders, with neuroinflammation shown to be an inhibitor of neurogenesis in the adult hippocampus [58,59]. Simvastatin has been shown to enhance neurogenesis in cultured adult neural progenitor cells, as well as in the dentate gyrus of adult mice through enhanced Wnt signalling [60]. In several models of traumatic brain injury (TBI), statins have shown promise in enhancing neurogenesis, and in some have been associated within reductions in injury-associated neurological sequelae, including reduced cognitive deficit. Both simvastatin and atorvastatin have been shown to enhance neurogenesis in the dentate gyrus following TBI in rats [61,62], which was associated with increased vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) expression [62], increased cellular proliferation and differentiation in the dentate gyrus [62], reduced delayed neuronal death in the hippocampus [61], and improved spatial learning [61,62].
Whilst FPP and GGPP appear to mediate some of the effects of statins, it is likely that the downstream small GTPase family of signalling molecules also play an important role. These molecules, including Ras, Rho, Rac, Rab and Rap, are involved in the prenylation process, whereby their interaction with proteins increases lipophilicity and facilitates interaction with cellular membranes. Depletion of FPP and GGPP through statin treatment, and subsequent inhibition of these small GTPase proteins, has been associated with both neuroprotective and neurotoxic effects in various cell and animal models. The modulation of Alzheimer amyloid-β precursor protein (APP) metabolism has been implicated as one possible mechanism of neuroprotection, with both in vitro and in vivo studies demonstrating statin-induced attenuation of cerebral amyloidosis and APP production [66,70,71]. It has been suggested that the inhibition of the Rho-associated coiled-coil kinase1/2 (ROCK) pathway by both simvastatin and atorvastatin is a possible mechanism for stimulated soluble APP (sAPP) shedding in mouse N2a.Swe neuroblastoma cells [70]. A similar study using the same cell line identified that simvastatin preferentially increase sAPPα over total sAPP, however had no effect on other cell lines including mouse primary neurons and human neuroglioma cells, suggested that this response may be unique to this cell line [72]. Based on results from this study which compared the effects of lovastatin and simvastatin on APP processing across a number of cell types from human and mice, it is likely that statin-induced effects on APP metabolism are cell type-dependent, thus specific in vitro data surrounding APP processing should be analysed cautiously [72].
Several lines of evidence suggest that the modulation of endothelial nitric oxide synthase (eNOS) and reduction of nitric oxide production by statins acts as a primary neuroprotective mechanism against stroke through the improvement of cerebral blood flow around cerebral penumbra [77,116]. In a mouse model of stroke, the protective effects of simvastatin (20 mg/kg/day, 14 days) on infarct size, cerebral blood flow and neurological function were eliminated following eNOS-knockout [117]. Statin-induced increases in eNOS have been attributed to GGPP inhibition [116], subsequent reduction in RhoA and Rac1 expression and the stabilisation of eNOS mRNA [118].
Atorvastatin has been identified across numerous studies as exerting beneficial effects against the neurological sequelae associated with SCI. Atorvastatin-treated rats (5 mg/kg, 2 h post-injury) have shown significant improvement in locomotor activity compared to control rats four weeks post-SCI in rats, which was attributed to reductions in early apoptosis at the injury site [159]. Similar studies in rats have identified additional mechanisms through which atorvastatin may exert its neuroprotective effects in SCI, including reduced blood-spinal cord barrier dysfunction through reduced RhoA/ROCK activity, reduced infiltration and expression of TNF-α, IL-1β and iNOS at the site of injury, reduced axonal degradation, myelin degradation, gliosis and neuronal death [160,161].
The MPV reduction was independently discovered by Albert Verley and the team of Hans Meerwein and Rudolf Schmidt in 1925. They found that a mixture of aluminium ethoxide and ethanol could reduce aldehydes to their alcohols.[2][3] Ponndorf applied the reaction to ketones and upgraded the catalyst to aluminium isopropoxide in isopropanol.[4]
The MPV reduction is believed to go through a catalytic cycle involving a six-member ring transition state as shown in Figure 2. Starting with the aluminium alkoxide 1, a carbonyl oxygen is coordinated to achieve the tetra coordinated aluminium intermediate 2. Between intermediates 2 and 3 the hydride is transferred to the carbonyl from the alkoxy ligand via a pericyclic mechanism. At this point the new carbonyl dissociates and gives the tricoordinated aluminium species 4. Finally, an alcohol from solution displaces the newly reduced carbonyl to regenerate the catalyst 1.
Each step in the cycle is reversible and the reaction is driven by the thermodynamic properties of the intermediates and the products. This means that given time the more thermodynamically stable product will be favored.
Several other mechanisms have been proposed for this reaction, including a radical mechanism as well as a mechanism involving an aluminium hydride species. The direct hydride transfer is the commonly accepted mechanism recently supported by experimental and theoretical data.[5]
The use of an intramolecular MPV reduction can give good enantiopurity.[8] By tethering the ketone to the hydride source only one transition state is possible (Figure 4) leading to the asymmetric reduction. This method, however, has the ability to undergo the reverse Oppenauer oxidation due to the proximity of the two reagents. Thus the reaction runs under thermodynamic equilibrium with the ratio of the products related to their relative stabilities. After the reaction is run the hydride-source portion of the molecule can be removed.
Several side reactions are known to occur. In the case of ketones and especially aldehydes aldol condensations have been observed. Aldehydes with no α-hydrogens can undergo the Tishchenko reaction.[6] Finally, in some cases the alcohol generated by the reduction can be dehydrated giving an alkyl carbon. 2ff7e9595c
Comments