Statins as Potentially Neuroprotective Agents: A Review

Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

“…These proinflammatory mediators are linked to reduced endothelial function, increased vascular permeability and cellular edema, neuronal ischemia, and ultimately cell death. 51 …”

“…49 Evidence for neuroprotective effects of statins have also been observed in preclinical studies of experimental stroke where treatment with rosuvastatin (0.2, 2, and 20 mg/kg) for 10 days reduced stroke volume by 27%, 56%, and 50%, respectively, in 129/SV WT mice that were subjected to 2-hour middle cerebral artery occlusion (MCAO). 50 In this section, we briefly review neuroprotective effects of statins, which are categorized based on 4 distinct biological mechanisms: (1) reduction in inflammation, 51,52 (2) attenuation of oxidative stress, 53 (3) inhibition of matrix metalloproteinase 9 (MMP-9) activity, 54,55 and (4) regulation of nitric oxide synthase activity. 56,57 An appreciation of how statins can modulate these pathologic processes is critical to assessing their efficacy as neuroprotective agents in the context of ischemic stroke.…”

“…These proinflammatory mediators are linked to reduced endothelial function, increased vascular permeability and cellular edema, neuronal ischemia, and ultimately cell death. 51 Generation of ROS during reperfusion is a critical event that leads to oxidative stress, BBB injury, and cerebral edema. 60 Hydroxyl (OH − ) and superoxide (O 2 − ) radicals damage cellular macromolecules, such as lipids, nucleic acids, and proteins, via lipid peroxidation.…”

Biocatalysis for the Production of Pharmaceutical Intermediates

“…27,[41][42][43][44] Besides lowering the LDL-C levels, and therefore reducing cardiovascular risk, 45 it has been reported that the use of statins has additional positive side effects. 46,47 Statins act as competitive inhibitors of HMG-CoA reductase, a key enzyme involved in cholesterol biosynthesis, 27,44,[47][48][49][50][51] and therefore are one of the most prescribed drugs today. 27,52 Presently, there are a number of statins on the market, being either natural or synthetic products, 35 and all having in common the pharmacophore syn-3,5-dihydroxy carboxylate side-chain.…”

“…28,35,67,48,51,54,58,[63][64][65][66] By using achiral substrates 28,48 the DERA enzyme catalyses the sequential aldol addition, which results in an enantiomerically pure lactol, a cyclized 2,4,6-trideoxyhexose, 27,[68][69][70][71][72] which is a valuable chiral synthon 40,64,69 used for the production of statin intermediates. 40,64,67,68,70,[73][74][75] Although the application of the DERA enzyme shows great potential in the production of statin intermediates, the enzyme demonstrates some major drawbacks for its practical application, 27,40,44,48,58,59 but due to the high interest in its application, the enzyme is being continuously re-engineered to have a better fit. 38,55,58,65,69,72 The DERA-based strategy is almost by default coupled with an oxidation step, in which the lactol is further oxidized into a lactone, such as cyclized 3,5-dihydroxyhexanoic acid, which is a more stable form of lactol 76 and thus presents a key product in the synthesis of statin intermediates.…”