Unfolding the pleiotropic facades of rosuvastatin in therapeutic intervention of myriads of neurodegenerative disorders

Abstract

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, are the drugs of choice for the pharmacotherapy of hyperlipidemia as well as for reducing atherosclerotic cardiovascular risk. 1 Statins inhibit the HMG-CoA reductase enzyme and therefore suppress the conversion of HMG-CoA into mevalonate-the first step in cholesterol biosynthesis. Following this step, low-density lipoprotein-cholesterol synthesis is lowered in hepatocytes, which consequently leads to a reduced blood cholesterol level. Despite this long known potent lipid-lowering effect, statins also possess lipid-independent pharmacological effects or pleiotropic effects. 2 Recently, there has been an increased interest in evaluating the potential use of statins for treating numerous neurological disorders. 3,4 Several pre-clinical and clinical trials substantiate the neuroprotective effect of statins in a plethora of neurological disorders such as Alzheimer's disease, Parkinson's, multiple sclerosis, epilepsy, spinal cord injury, depression, cognitive dysfunction, and stroke. 3-6 Possible reasons behind the neuroprotective effect of statins may be attributed to their anti-inflammatory, antioxidant, anti-apoptotic, and anti-excitotoxicity activities. 7 Interestingly, of all the statins, rosuvastatin is comparatively the most potent. It exhibits greater affinity for the active site of HMG-CoA reductase as evident in STELLAR, DISCOVERY and the Discovery Belux studies. 8 Although statins contain both hydrophilic and lipophilic moieties, the hydrophilic nature of rosuvastatin is more prominent. 9 Rosuvastatin possesses an atypical N-methyl N-linked sulphonamide moiety along with a wholly substituted pyrimidine nucleus. Further, X-ray crystallography studies have revealed that rosuvastatin had the most number of protein-ligand interactions when compared to any other member of this family (Figure 1). 10 It is metabolized slowly by hepatic enzymes, particularly CYP2C19 and CYP2C9 and its duration of action and plasma half-life are higher than any other statin. 11 Escalating evidence suggests that rosuvastatin, apart from its hypolipidaemic effects, exerts multiple beneficial pleiotropic immunomodulatory, anti-inflammatory, anti-apoptotic and anti-excitotoxic actions. 12 These pleiotropic, cholesterol-independent effects include increase in endothelial NO synthase (NOS) and tissue-type plasminogen Summary Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitor, and one of the most popular antihyperlipidemic medications have been found to possess pharmacodynamic activities much different from its usual indication. Recent research studies have revealed the efficacy of rosuvastatin in attenuating neuroinflammation, reducing the progression of Alzheimer's disease, providing protection against cerebral ischaemia and spinal cord injury as well as ameliorating epilepsy.Mechanisms behind the neuroprotective potential of rosuvastatin can be attributed to its pleiotropic effects, independent of its abili...

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