Statins, such as atorvastatin and simvastatin, inhibit cholesterol biosynthesis by inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase enzyme. Low dose of atorvastatin given 24 hours after stroke enhanced neurogenesis, angiogenesis, and synaptogenesis in rats. These effects were mediated and/or marked by significant increase in vascular endothelial growth factor (VEGF), cyclic guanosine monophosphate (cGMP), and the synaptic protein, synaptophysin (Chen et al., 2003). Statins were found to render cortical neurons more resistant to NMDA-induced excitotoxicity. Atorvastatin leads to activation of endothelial nitric oxide synthase (eNOS) which promotes nitric oxide (NO) production. NO activates soluble guanylyl cyclase leading to the formation of cGMP. NO/cGMP signaling promotes axonal sprouting, synaptogenesis, neurogenesis, and angiogenesis. Statins also increase the level of VEGF-VEGFR2, BDNF (brain-derived neurotrophic factor), tissue plasminogen activator (tPA), phosphatidylinositol 3'-kinase (PI3K)-AKT, and small G proteins in the ischemic brain (Chen et al., 2005). These proteins regulate vascular and neurogenic, neuroprotective, and neurorestorative effects. Atorvastatin (Lipitor) treatment after stroke induces the proliferation of the progenitor cells (neuroblasts) of the subventricular zone (SVZ) and their migration to the ischemic border (around the infarction) and differentiation into neurons.
Prophylactic treatment with HMG-CoA reductase inhibitors reduces cerebral infarct size, enhances cerebral blood flow, and improves neurological outcome in mice with normal blood level of cholesterol (Endres et al., 1998). Most of the neural effects of statins are cholesterol-independent such as regulation of neural progenitor cells, inhibition of tissue inflammatory responses, immunomodulatory actions, increased NO bioavailability, and antioxidant activities.
Statins and Spinal Cord Injury: Spinal cord injury (SCI) is a complex pathology leading to neuronal apoptosis and loss, axonal destruction, oligodendrocyte apoptosis, demyelination, reactive astrocytosis at the lesion site. These events are mediated by proinflammatory cytokines and nitric oxide toxicity. Following SCI, there is increased expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor α (TNFα), and interleukin 1β (IL-1β). Atorvastatin treatment of SCI models of rats diminished SCI-induced iNOS, TNFα, and IL-1β expression and attenuated SCI-induced tissue necrosis, neuronal and oligodendrocyte apoptosis, demyelination, and reactive gliosis. Furthermore, atorvastatin improved functional recovery of the treated rats.
Statins and Multiple Sclerosis: Multiple sclerosis is a neuroinflammatory disease characterized by increased expression of proinflammatory cytokines and inducible nitric oxide synthase (iNOS). These cytokines include tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). It has been found that a statin, named lovastatin, inhibits the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia and macrophage that are involved in the pathogenesis of experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). This highlights the therapeutic importance of lovastatin in ameliorating the neuroinflammatory disease process in the central nervous system of EAE rats. Administration of lovastatin inhibited the expression of iNOS, TNF-alpha and IFN-gamma in the CNS of EAE rats and improved the clinical signs of EAE indicating that this statin may have a therapeutic potential in the treatment of neuroinflammatory diseases like MS.
References
- Chen J, Chopp M. Neurorestorative treatment of stroke (2006): cell and pharmacological approaches.NeuroRx. 3: 466-73
- Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A, Katakowski M, Lu M, Chopp M (2005):Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice.J Cereb Blood Flow Metab. 25: 281-90
- Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, Zhang C, Lu M, Katakowski M, Feldkamp CS, Chopp M (2003): Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke.Ann Neurol. 53: 743-51
- Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK (1998): Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 95: 8880.
- Stanislaus R, Pahan K, Singh AK, Singh I (1999): Amelioration of experimental allergic encephalomyelitis in Lewis rats by lovastatin. Neurosci Lett. 1999 269: 71-4.
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