Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system

Abstract

HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.

Antiretrovirals, Methamphetamine, and HIV-1 Envelope Protein gp120 Compromise Neuronal Energy Homeostasis in Association with Various Degrees of Synaptic and Neuritic Damage

“…Neuronal damage found in neuro-AIDS can have different origins, ranging from neurotoxins and viral proteins produced by HIV-infected cells in the CNS (44,(68)(69)(70)(71) to toxicity induced by the use of both therapeutic and recreational drugs (14,17,37,38,72). In this study, we assessed for the first time experimentally the contribution to neuronal injury of METH, ARVs, and an established viral neurotoxin, HIV-1 gp120, in combination.…”

“…Several other studies have provided direct evidence that antiretroviral drugs can exert neurotoxic effects in connection with oxidative stress, dysregulation of Ca 2ϩ homeostasis, and alteration of mitochondrial respiration (14,17,62,(73)(74)(75)(76)(77)(78). Furthermore, similar to HIV-1 gp120, the earliest antiretroviral drug, AZT, has been shown to impair neurogenesis (79-81), besides affecting cerebrocortical mitochondria (82).…”

“…Several studies demonstrated toxicity of ARV compounds, associated with mitochondrial function and the capacity to generate ATP (11)(12)(13), with neuronal dysfunction (14), with peripheral neuropathy (15,16), and with oxidative stress in the CNS (17). In addition, recent studies found that discontinuation of ARV use in HIV patients with controlled viral loads unexpectedly resulted in significant improvements in neurocognitive function (16,(18)(19)(20).…”

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

“…[190][191][192] Recent data further explored this hypothesis and the production of oxygen reactive species was confirmed in pigtail macaques and rats in vivo (with the exposure to zidovudine, saquinavir and ritonavir). [193] PIs and efavirenz have been associated with glucose and metabolic disturbances eventually leading to dyslipidaemia, glucose intolerance and to abnormal fat distribution (lipodystrophy); the cumulative exposure to PIs has further being implicated in the increasing cardiovascular event observed in HIV-positive patients. [194] Previous studies suggest that HIV-infected patients are at increased risk of ischemic cerebrovascular disease, potentially caused by infective vasculitis, brain opportunistic diseases, cardiac embolism, hypercoagulopathy, or HIV infection itself.…”

Enhanced antagonism of BST-2 by a neurovirulent SIV envelope

“…Other reports suggest that CNS pathology could be the result of chronic immune activation during cART, causing bystander cell death in the CNS (10,11). In addition, some reports suggest direct toxicity of antiretroviral drugs in the CNS (12,13).…”