Cholesterol-Depleting Statin Drugs Protect Postmitotically Differentiated Human Neurons against Ethanol- and Human Immunodeficiency Virus Type 1-Induced Oxidative Stress In Vitro

Abstract

The AIDS-related dementia characterized by cognitive dysfunction, motor neuron disease, coordination abnormalities, and other neurological signs and symptoms develops in many human immunodeficiency virus type 1 (HIV-1)-infected individuals (17, 58). The molecular mechanisms involved in these HIV-1-associated dysfunctions of the central nervous system (CNS) remain incompletely explained and controversial (42,45). Studies have demonstrated that although the major reservoirs for productive infection within the CNS of HIV-1-infected individuals are microglia and monocytes/macrophages, infection of other CNSbased cell types, such as microvascular endothelial cells and neurons, also appears to occur (44,57,92). The role of lymphocytes in AIDS dementia has also been described previously (59,67,68). Of note, viral replication in cerebrospinal fluid is considered to be a marker for the severity of AIDS-related neurodegeneration (16,20). The CNS tissues are protected from the periphery by a structure known as blood-brain barrier (BBB), which limits the passage of solutes as well as infections into the brain (10). The tight junctions of brain microvascular endothelial cells strengthen the functional impermeability of BBB. Under certain pathological conditions, the BBB becomes compromised, providing access for infections/infected cells into the brain (64). The passage of HIV-1 entry into the brains of AIDS patients in vivo is not quite clear and is supposed to involve both free viruses and virally infected cells (4,89,91).HIV-1-infected individuals are under chronic oxidative stress, and antioxidants have proved to ameliorate infectionassociated oxidative stress. (81, 84). Oxidative stress involves

A lipid storage–like disorder contributes to cognitive decline in HIV-infected subjects

“…For example, pretreatment of neurons with HMG-coenzyme A reductase inhibitors (the rate-limiting enzyme for cholesterol synthesis) has been shown to protect neurons from HIV by reducing the induction of stress-associated pathways including Hsp70, isoprostanes, and total nitrate levels. 29 A second intriguing possibility is that dietary manipulations could modify brain sphingolipid and sterol content. Age-associated accumulations of ceramides and long-chain glycosphingolipids can be reduced by caloric restriction, or by a diet rich in n-3 polyunsaturated fatty acids.…”

Prehospital HMG Co-A reductase inhibitor use and reduced mortality in hemorrhagic shock due to trauma

“…These mechanisms appear to be active in the physiologic response to shock caused by sepsis [10,11]. In animal models, the mechanism appears to be the reduction of inflammatory mediators and final common pathway products, such as heat shock proteins, tumor necrosis factor-a, multiple interleukins, nuclear factor jB, nitric oxide synthetase (and, therefore, nitric oxide), and oxidized low-density lipoproteins [1][2][3][4][5][6][7][8][9]. These biologic end products indicted as causative in the physiologic derangements of septic shock are also associated with hemorrhagic shock as a putative final common pathway to organ dysfunction and death.…”

“…Increasing amounts of research suggest that this class of drugs may have many other potential physiological effects besides the blockade of HMG Co-A reductase. Animal studies show that statins have potent anti-inflammatory effects [1][2][3] by reducing a vast number of inflammatory mediators, including heat shock proteins [4], tumor necrosis factor-a, various interleukins, nitric oxide synthetase, oxidized low-density lipoproteins, and oxygen free radicals [5][6][7][8][9]. The effects on humans have been studied retrospectively.…”

Role of MutS homolog 2 (MSH2) in intestinal myofibroblast proliferation during Crohn's disease stricture formation

“…The antioxidant and anti-inflammatory capacity of statins have been demonstrated in vitro in neurology and cardiology fields. It has been demonstrated that statins may protect neurons against ethanol-mediated injury as well as human immunodeficiency virus type 1-induced oxidative stress (1). Mechanistically, statins have been shown to downregulate expression of Bcl-2, which was linked with increased apoptosis in mesenchymal cells (5,38).…”