1. INTRODUCTION:

Statins are having a promising ability to accommodate a new therapeutic goal for multitudinal neurological disorders at present. It is well full-fledged that statins decrease levels of cholesterol and anticipate CHD. In addition to that, attestations proposed that in addition to antioxidant, anti-inflammatory and anti-platelet effects, statins have supplementary possessions suchlike endothelial protection through action on the nitric oxide synthase system. Not only in stroke but also these possessions might have potential therapeutic association in neurological disorders such as Alzheimer disease, Parkinson's disease, multiple sclerosis and primary brain tumors. The inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and thus the restriction of the enzyme in the biosynthesis of cholesterol is the principal mechanism of action of statins. That results in the growth in a number and activity of LDL receptors, and decrease in this cholesterol fraction in the plasma as a consequence [1]

Statins also precisely regulate endothelial nitric oxide synthase expression, autonomous of cholesterol levels, exclusively from cholesterol-dependent mechanisms of action. [2, 3].

2.1 STATINS AND STROKE:

By modulation of pre-cerebral atherothrombosis in the carotid artery and the aorta and therefore anticipating artery-to artery thromboembolism and plaque division by restricting coagulation at its various levels, degenerating tissue factor, innovation of prothrombin to thrombin activity etc statins through an array of mechanisms can decrease strokes of various etiology. [4].

Vaughan et al. [5] in experimental models of ischemic stroke have shown that size of brain infarct is reduced by statin therapy and by direct up-regulation of brain endothelial NO synthase, the ameliorate neurologic effect is decresed. Additional to that he showed the anti-inflammatory actions of statins that probably will contribute to neuroprotection and stroke prevention.

The Pravastatin Lipids and Atherosclerosis in the Carotids II (PLACII) study also established a cognent decline in carotid intimal-medial thickness in pravastatin-treated patients. The impact of statin treatment on aortic atherosclerosis has not been broadly analysed [5]. Decrease in stroke incidence by statins like pravastatin, simvastatin [6] and lovastatin were also accustomed in short-term clinical studies [7].

In the experiment conducted by The Large Prospective Studies Collaboration Group, there was no correlation between cholesterol and stroke. However, they did not categorize between ischemic and hemorrhagic stroke [8]. Cucchiara et al. [8] have shown that the opposing effects of cholesterol on ischemic versus hemorrhagic stroke risk may confuse efforts to compare cholesterol levels with stroke except stroke type ( i.e. hemorrhagic vs. ischemic) is taken into account.

In the Cholesterol and Recurrent Events (CARE) Trial, the pravastatin group had a 31% lower incidenceof all strokes, even though again the incidence of lethal strokes was about the same. Summarizing, there was no increase in the rate of hemorrhagic stroke [9].

On Comparisons of statins, Laufs et al. [10] have showed the results that eshtablish that rosuvastatin is at least as effective as simvastatin and atorvastatin and provided better protection than lovastatin and mevastatin in the mouse middle cerebral artery (MCA) stroke model.

2.2 STATINS AND AZD:

In 2013, as many as 5 million Americans were living with Alzheimer’s disease [11]. By 2050, this number is calculated to reach to 14 million, a almost three-fold increase [11]. Increased levels of β-amyloid and apolipoprotein E have been found to be affliated with AD [12-14]. Inclusion to that, atherosclerosis and elevated levels of plasma total cholesterol or triglyceride and low-density lipoprotein cholesterol (LDL-C) exasperated the symptoms of AD.

According to a current study, Alzheimer’s is evoked by a lower intake in omega-3 fatty acids, found in fish [15]. The study farther explicated that cholesterol esters are a common pool for fatty acids in plasma. Inpoint of fact, it is found that there are considerably lower numbers of fatty acids, phospholipids and esterified cholesterol in the CSF of accustomed Alzheimer’s subjects [16].

Dr. Seneff also asserted that lower levels of fatty acids are found in the CSF in patients with Alzheimer’s. In point of fact, it was bring into being that about Alzheimer’s patients have less that 20% of the concentration of fatty acids in CSF compared to non-Alzheimer’s patients [17]. Taling into account that statins can additionally reduce this number by lowering the carry capacity of fats by cholesterol, it should be made alert that statins can possibly pose a threat to provoking Alzheimer’s rather than preventing it.

Follow-up studies in humans have currently suggested that patients getting statin therapy have a reduced incidence of dementia. Cholesterol lowering with statins may have potential therapeutic benefit in AD. Simvastatin has been shown to decrease plasma levels of apoE in patients with senile AD, though cerebrospinal fluid levels of apoE were not significantly replaced[18,19].

2.3 STATINS AND PARKINSONS DISEASE:

Many studies have shown that statins can decrease the incidence of PD, although cholesterol level may be associated with a higher incidence of this illness. Some clinical studies have reported that statin use is irrelevant to the progression of PD and dementia [20-22].

In a meta-analysis of observational studies, statin use significantly reduced the risk of PD by 23% [21]

One study showed the statins can reduce the elevation of the levodopa equivalent daily dose over 2 years in PD patients, which suggested that statin use may be involved in the onset and development of PD [23].

A 12-year follow-up of 644 incident PD cases found that regular use of statins was associated with a modest decrease in PD risk [24].

Koob found that lovastatin could reduce alpha-synuclein aggregation, the neuropathologic hallmark of PD, in a transgenic model [25].

2.4 STATINS AND MULTIPLE SCLEROSIS:

In a review done, eight trials were included [26 ] five of statin add-on to interferon (IFN)-β treatment in RRMS, one of statin monotherapy in CIS, one of statin monotherapy in optic neuritis (ON)/CIS, and one of statin monotherapy in secondary progressive MS (SPMS)]. Three trials with eligible characteristics had not been published in peer-reviewed journals and were therefore excluded. In CIS and SPMS due to the less number of trials, meta-analysis of primary outcomes was only performed for RRMS studies. Meta-analysis showed no significant effect of statin add-on to IFNβ therapy. Actually, a trend towards a rise in disease activity was exhibited in the statin group with commendations to new T2 lesions, relative amount of patients with relapse, and whole brain atrophy but not for EDSS progression.

An open label clinical trial of simvastatin and atorvastatin for SM disclosed a significant diminishing in the number and volume of new MRI lesions and a agreeable safety profile [27].

In vitro studies with human peripheral blood lymphocytes disclosed that the anti-inflammatory effects of simvastatin, lovastatin, and mevastatin are strong and eivalent with those of interferon -1b. Some proinflammatory effects caused by heavy secretion of interferon and interleukin 12 were also noticed. The blending of statins and interferon -1b had hooking anti-inflammatory effects [28, 29].

In addition, statins abridge T-cell proliferation, under expression of activation surface markers and induce production of the cytokine IL-4. At present, simvastatin is being tested in a phase II clinical trial in SM [30].

2.5 STATINS AND VASCULAR DEMENTIA:

Statins can have neuroprotective effects in patients with vascular dementia (VaD) [31]; these effects have been well recorded, the mechanisms of which may be connected with modulation of nitric oxide (NO).

Nitric oxide can anticipate the advancement of VaD by harmonising the cerebral blood flow. Lower NO levels can lead to cognitive drop in serum of VaD patients [32], whereas statins can increase NO generation [33].

Different mechanisms have been contemplated to annotate the protective role of statins in eNOS [34,35].

In an Sprague Dawley (SD) rat model of transient middle cerebral artery occlusion (tMCAO), rosuvastatin inhibited the upregulation of glycoprotein 91 (phox) and p22phox, the phosphorylation of nuclear factor-kappa B, and the induction of cyclooxygenase 2 and inducible nitric oxide synthase [36].

Hypercholesterolemia and atherosclerosis can actuate eNOS dysfunction and decrease the expression of eNOS and NO [37], when it fact, statins can prevent cognitive impairment by their anti-atherosclerotic effects [38]. Statins can also prevent the advncement of vascular-related cognitive impairment by an antiplatelet mechanism [39]. Treatment with statins can decrease the incidence of VaD [40].

The confederation between blood pressure and dementia appears to be complex. The impairment of cognitive function has been associated with both high and low blood pressure levels in older subjects [41].

Age-related changes in both blood pressure level and cognitive function, as well as vascular brain damage and systemic arterial aging, may have a confusing role. Hypertension is an freewheeling risk factor for mild cognitive impairment [42].

A previous systematic review showed that antihypertensive medication could decrease the risk of vascular dementia, by a mechanism that may be associated with reducing the risk of stroke through improved blood pressure control [43]. One study found that higher ambulatory pulse pressure is associated with poor cognitive outcomes [44].

3. CONCLUSION:

This review has confabulated current experimental attestations suggesting that some mechanisms of action of statins can protect from ischemic stroke. To survey the initial observations suggesting the neuroprotective properties of statins, additional investigation using neuroimaging studies and serial cognitive evaluation studies are authorised. Statins may show distinctive neuroprotective effects in neurodegenerative diseases,when taken together.

4. ABBREVIATIONS:

CHD : Coronary Heart Disease

LDL : Low Density Lipoproteins

AZD : Alzheimer’s Disease

CSF : Cerebro Spinal Fluid

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Received on 19.04.2018 Modified on 12.05.2018

Research J. Pharm. and Tech 2018; 11(8): 3581-3584.

DOI: 10.5958/0974-360X.2018.00659.5