Intrastriatal administration of human immunodeficiency virus‐1 glycoprotein 120 reduces glial cell‐line derived neurotrophic factor levels and causes apoptosis in the substantia nigra

Abstract

Uninfected neurons of the substantia nigra (SN) degenerate in human immunodeficiency virus (HIV)-positive patients through an unknown etiology. The HIV envelope glycoprotein 120 (gp120) causes apoptotic neuronal cell death in the rodent striatum, but its primary neurotoxic mechanism is still under investigation. Previous studies have shown that gp120 causes neurotoxicity in the rat striatum by reducing brain-derived neurotrophic factor (BDNF). Because glial cell line-derived neurotrophic factor (GDNF) and BDNF are neurotrophic factors crucial for the survival of dopaminergic neurons of the SN, we investigated whether gp120 reduces GDNF and BDNF levels concomitantly to induce apoptosis. Rats received a microinjection of gp120 or vehicle into the striatum and were sacrificed at various time intervals. GDNF but not BDNF immunoreactivity was decreased in the SN by 4 days in gp120-treated rats. In these animals, a significant increase in the number of caspase-3-positive neurons, both tyrosine hydroxylase (TH)-positive and -negative, was observed. Analysis of TH immunoreactivity revealed fewer TH-positive neurons and fibers in a medial and lateral portion of cell group A9 of the SN, an area that projects to the striatum, suggesting that gp120 induces retrograde degeneration of nigrostriatal neurons. We propose that dysfunction of the nigrostriatal dopaminergic system associated with HIV may be caused by a reduction of neurotrophic factor expression by gp120. '

CXCR4 and CXCL12 Expression is Increased in the Nigro-Striatal System of Parkinson’s Disease

“…However, CXCR4 signaling can induce neuronal cell death even in the absence of other pro-inflammatory cytokines. In fact, in the rat striatum, stimuli that activate CXCR4 but not other inflammatory responses have been shown to activate caspase-3, reduce DA levels in the striatum, and induce cell death and tissue loss in the SN and STR Nosheny et al 2006). Therefore, it is conceivable that CXCL12 may be neurotoxic to DA neurons either by a direct action on DA neurons expressing CXCR4 or by inducing the release of cytokines and other neurotoxins from microglia, which, in turn, will reduce the survival of DA neurons.…”

Driving GDNF expression: The green and the red traffic lights

“…The lack of effect of gp120 on striatal GDNF suggest that gp120 may not affect GDNF synthesis, but that decreased GDNF levels in the substantia nigra may be due to a reduced transport from the striatum. It was therefore proposed that dysfunction of the nigrostriatal dopaminergic system associated with HIV may be caused by a reduction of neurotrophic factor support induced by gp120 due to interference with neurotrophic factor accumulation, release, or signalling (Nosheny et al, 2006). However, the mechanism involved in the gp120-induced GDNF reduced levels in the substantia nigra remains to be elucidated.…”

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“…Given that HIV preferentially involves sub-cortical structures (Becker et al, 2011; Itoh, et al, 2000; Nosheny, Bachis, Aden, De Bernardi, & Mocchetti, 2006), it may be hypothesized that processing speed deficits are still central to HAND in the CART era. HIV infection is associated with reduced frontostriatal connectivity (Melrose, Tinaz, Castelo, Courtney, & Stern, 2008), which is the neural circuitry that regulates information processing through neurotransmission (Tekin & Cummings, 2002).…”