Original ContributionHIV proteins (gp120 and Tat) and methamphetamine in oxidative stress-induced damage in the brain: Potential role of the thiol antioxidant N-acetylcysteine amide
Introduction
HIV-1-associated-dementia (HAD), a neurological syndrome characterized by cognitive deficits and motor and behavioral dysfunctions, is one of the most common complications associated with human immunodeficiency virus (HIV-1) infection [1], [2], [3], [4]. A third of the adults and half of the children with HIV infection have been reported to develop HAD [5]. HAD is one of the most common causes of dementia worldwide among people aged 40 years or less, and is a significant independent risk factor in death due to HIV infection [6]. Though the clinical and pathological conditions of HAD have been well characterized, the pathogenesis of the progression of the disease is not well understood.
The blood-brain barrier (BBB), defining an interface between the central nervous system and the blood, performs the essential function of shielding the brain from toxic substances and is believed to play an important role in the development of HAD [7], [8]. Studies have shown that disruption of the BBB is more frequent in HAD patients when compared with non-demented HIV patients or control patients [9]. Furthermore, the HIV-1 envelope glycoprotein (gp120) and transregulatory protein (Tat) of HIV-1 are neurotoxic and cytotoxic and have been implicated in the development of HAD [10], [11]. Previous studies have reported that oxidative stress-induced by gp120 and Tat leads to the disruption of the BBB [12]. A dose-dependent increase in oxidative stress and decrease in intracellular glutathione have been observed in brain endothelial cells treated with Tat [9].
In addition to this, many HIV-positive patients use addictive drugs like methamphetamine (METH), which is a well known neurotoxicant [13], [14], [15]. METH has been reported to promote dopamine release in the nucleus accumbens, leading to degeneration of the striatal dopamine terminals [16], [17]. Further, dopamine oxidation leads to the formation of reactive oxygen species, which disturbs the antioxidant defense mechanism in the body leading to oxidative stress-induced damage [18]. Overproduction of superoxide radicals and a decrease in antioxidant enzyme activity have been observed in mice treated with METH. Degeneration of various regions of the brain, particularly the BBB, has also been reported due to METH abuse. Brain degeneration is associated with modifications of the BBB [19]. Disruption of the tight junctions (TJ) is one of the common causes of BBB dysfunction. TJs are composed of the tight junction proteins (Occludin, Claudin, Zona Occludens), and play an important role in maintaining the structural integrity and low permeability of the BBB [20]. Disruption of the BBB has been reported to contribute to the progression of various neurological diseases like multiple sclerosis, Alzheimer's and Parkinson's disease [21]. Further, oxidative stress has also been reported to be an important factor in BBB dysfunction [22]. Under physiological conditions, the integrity of the BBB is protected from oxidative stress because the BBB has high levels of antioxidant enzymes. However, under oxidative stress, depletion of these antioxidant enzymes leads to the increase in permeability and loss of integrity of these endothelial cells [23]. Supplementation of antioxidants is becoming increasingly popular in oxidative stress-related disorders. Thiol antioxidants like cysteine, glutathione and N-acetylcysteine (NAC) have been shown to provide a protective effect against stress-related disorders [24], [25], [26], [27]. However, some of these thiols, such as NAC, have been reported to have several side effects and toxicities such as suppressing respiratory burst, and causing toxic accumulation of ammonia in the liver [28], [29]. In addition, bioavailability of NAC is very low because its carboxylic group loses its proton at physiological pH, making the compound negatively charged and consequently less permeable. N-acetylcysteine amide (NACA), a modified form of NAC, where the carboxyl group has been replaced by an amide group, has been found to be more effective in neurotoxic cases because of its ability to permeate cell membranes and the BBB [29].
Since METH has been shown to induce oxidative stress, it was of significant interest to understand if METH potentiated the oxidative stress induced by HIV-1 proteins gp120 and Tat at the BBB. Also, the efficacy of the thiol antioxidant NACA to confer protection to animals exposed to gp120, Tat and METH, and to abrogate the oxidative stress-induced damage at the BBB was investigated.
Section snippets
Materials
CD-1 mice were obtained from the in-house colony at the VA medical center-St. Louis. N-acetylcysteine amide (NACA) was provided by Dr. Glenn Goldstein (David Pharmaceuticals, New York, NY, USA). N-(1-pyrenyl)-maleimide (NPM) was purchased from Sigma (St. Louis, MO). High-performance liquid chromatography (HPLC) grade solvents were purchased from Fisher Scientific (Fair Lawn, NJ). All other chemicals were purchased from Sigma (St. Louis, MO), unless stated otherwise.
Animal experiments
Male CD-1 mice (30-35 g, 7
Effects of HIV proteins, METH and NACA on GSH levels in the brain
The effects of HIV proteins gp120 and Tat in the brain were studied. Compared to the controls and the NACA-alone treated group, the gp120- and METH-treated animals had decreases (∼ 20%) in the GSH levels in their brains. A significant and drastic decrease (∼ 85%) in the levels of GSH was observed in animals treated with Tat protein alone. In this study, animals treated with gp120 + Tat and gp120 + Tat + METH, also experiences significant decrease in GSH levels, as compared to the controls or the
Discussion
In the recent years, METH use has been implicated in worsening of HIV associated neurological impairments, especially HAD [43], [44], [45], [46], [47]. The neurotoxic effect of METH increases dopamine and glutamate formation in the brain that, in turn, mediates damage to the dopamine neurons through the formation of toxic ROS [48], [49], [50], [51]. The HIV viral proteins (gp120 and Tat) have also been reported to increase oxidative stress in the brain [12]. Although both HIV viral proteins and
Acknowledgments
Dr. Ercal is supported by 1 R15DA023409-01A2 from the NIDA, NIH. The contents of this paper are solely the responsibility of the authors and do not necessarily represent official views of the NIDA or NIH. Dr. Banks is supported by VA Merit Review and R01 AG029839. The authors appreciate the efforts of Barbara Harris in editing the manuscript. HIV-1 Tat and HIV-1 Bal gp120 protein was obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH.
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