Gene delivery of antioxidant enzymes inhibits human immunodeficiency virus type 1 gp120-induced expression of caspases

Abstract

Caspases are implicated in neuronal death in neurodegenerative and other Central Nervous System (CNS) diseases. In a rat model of HIV-1 associated neurocognitive disorders (HAND), we previously characterized HIV-1 envelope gp120-induced neuronal apoptosis by TUNEL assay. In this model, neuronal apoptosis occurred probably via gp120-induced reactive oxygen species (ROS). Antioxidant gene delivery blunted gp120-related apoptosis. Here, we studied the effect of gp120 on different caspases (3, 6, 8, 9) expression. Caspases production increased in the rat caudate-putamen (CP) 6h after gp120 injection into the same structure. The expression of caspases peaked by 24h. Caspases colocalized mainly with neurons. Prior gene delivery of the antioxidant enzymes Cu/Zn superoxide dismutase (SOD1) or glutathione peroxidase (GPx1) into the CP before injecting gp120 there reduced levels of gp120-induced caspases, recapitulating the effect of antioxidant enzymes on gp120-induced apoptosis observed by TUNEL. Thus, HIV-1 gp120 increased caspases expression in the CP. Prior antioxidant enzyme treatment mitigated production of these caspases, probably by reducing ROS levels.

Nicotine mediates expression of genes related to antioxidant capacity and oxidative stress response in HIV-1 transgenic rat brain

“…This formation activates caspase-9-mediated apoptotic signaling cascades during neurodegeneration (Fratiglioni and Wang, 2000). HIV-1 proteins trigger the apoptotic signaling cascades by decreasing the levels of antioxidant enzymes with uncompensated ROS production (Louboutin et al , 2012). Our results partially confirm the aforementioned findings and show that HIV-1 proteins decreased the expression of antioxidant enzymes in the NAc (Gstm5) and up-regulated the Gsta6 in the VTA.…”

“…The balance between oxidant species and removal of oxidants by the antioxidant enzymes determines the ROS-mediated apoptosis signaling in neurons. Multiple in vitro and in vivo studies have demonstrated the neuroprotective effect of Sod1 overexpression in neurodegeneration including HAND (Boven et al , 1999; Louboutin et al , 2012). Results demonstrated that increased levels of Sod1 induced a decrease in ROS levels that lead to an enhanced resistance to caspase-mediated apoptosis in neurons.…”

Plasma gelsolin protects HIV-1 gp120-induced neuronal injury via voltage-gated K+ channel Kv2.1

“…Another possibility is pGSN blocks the interaction between gp120 and Kv2.1 channel as viral proteins were found to interact with ion channels (Qiao and McMillan, 2007). In addition, pGSN may protect neurons through inhibition of gp120-mediated activation of caspases since gp120 has been shown to induce neuronal injury via activation of caspases (Louboutin et al, 2012; Tun et al, 2007) and GSN has been reported to, in complex with phosphatidylinositol 4, 5-biphosphate, inhibit caspase activity and retard apoptotic progression (Azuma et al, 2000). As to the site of pGSN action, it appears that pGSN acts extracellularly since pGSN inhibited gp120-induced shift of outward K + current inactivation curve shortly after brief bath perfusion of pGSN (Fig.…”

Revolutionary Impact of Nanodrug Delivery on Neuroscience

“…The preparation of these two types of drugs is closely connected. Researchers are studying the interactions of different neurotransmitters [103], neurohormones [104], neuromodulators [105], enzymes [106], second messengers [107], co-transporters [108,109], ion channels [110], and receptor proteins [111] in the central and peripheral nervous systems to develop drugs to treat many different neurological disorders, including pain [112], neurodegenerative diseases such as Parkinson's disease [113] and Alzheimer's disease [114], psychological disorders [115], addiction [116], and many others.…”