Platelet-Derived Growth Factor-BB Restores Human Immunodeficiency Virus Tat-Cocaine-Mediated Impairment of Neurogenesis: Role of TRPC1 Channels

Abstract

Platelet-derived growth factor-BB (PDGF-BB) has been reported to provide tropic support for neurons in the central nervous system (CNS). However, whether PDGF-BB regulates neurogenesis especially in the context of HIV-associated neurological disorder (HAND) and drug abuse, remains largely unknown. In this study we demonstrate that pre-treatment of rat hippocampal neuronal progenitor cells (NPCs) with PDGF-BB restored proliferation that had been impaired by HIV Tat & cocaine via the cognate receptors. We identify the essential role of transient receptor potential canonical (TRPC) channels in PDGF-BB-mediated proliferation. Parallel but distinct ERK/CREB, PI3K/Akt signaling pathways with downstream activation of mTOR/4E-BP & p70S6K and NF-kB were critical for proliferation. Blocking TRPC 1 channel suppressed PDGF-mediated proliferation as well as PDGF-BB-induced ERK/CREB and mTOR/4E-BP & p70S6K activation thereby underscoring its role in this process. In vivo relevance of these findings was further corroborated in Tat transgenic mice wherein hippocampal injection of recombinant rAAV2-PDGF-B restored impaired NPC proliferation that was induced by Tat & cocaine. Together these data underpin the role of TRPC 1 channel as a novel target that regulates cell proliferation-mediated by PDGF-BB with implications for therapeutic intervention for reversal of impaired neurogenesis inflicted by Tat and cocaine.

Direct interaction of receptor tyrosine kinases, EphA4 and PDGFRβ, plays an important role in the proliferation of neural stem cells

“…To further explore the EphA4-mediated signaling pathways and their biological functions PDGF, as a novel factor for neuron protection and neuron growth, plays a key role in regulating neurogenesis and hence is the mutation target of neurodegenerative diseases. [28][29][30][31] Bush et al reported that PDGF-BB is implicated in playing key roles in neural stem/progenitor cell (NPC) proliferation and neurogenesis under the condition of HIV-associated neurological disorders. They observed that PDGF-BB could restore the hippocampal NPC proliferation through cognate receptors of HIV Tat-cocaine.…”

“…42 PDGF-BB plays key roles in the in vitro proliferation 30 and neuronal differentiation of neural stem cells derived from the embryonic hippocampus. 32 Furthermore, PDGF signaling prevents the cerebral hemisphere from cryogenic injury in adulthood mice.…”

The impact of HIV-1 on neurogenesis: implications for HAND

“…They demonstrated that pretreatment of rat hippocampal NPCs with PDGF-BB restored NPC proliferation which had been damaged by HIV Tat-cocaine. In their model, they found that the transient receptor potential canonical (TRPC) channels in PDGF-BB mediated the proliferation of NPCs [44]. They further substantiated their findings in vivo utilizing Tat transgenic mice by showing that the hippocampal injection of recombinant adeno-associated virus (AAV) 2-PDGF-2 rescued impaired NPC proliferation that was induced by Tat-cocaine.…”

“…In a study by Yao and colleagues, they sought to determine whether PDGF-BB regulated neurogenesis within the context of HAND and drugs of abuse [44]. They demonstrated that pretreatment of rat hippocampal NPCs with PDGF-BB restored NPC proliferation which had been damaged by HIV Tat-cocaine.…”

“…They further substantiated their findings in vivo utilizing Tat transgenic mice by showing that the hippocampal injection of recombinant adeno-associated virus (AAV) 2-PDGF-2 rescued impaired NPC proliferation that was induced by Tat-cocaine. These findings identified the TRPC1 channel as a novel target which regulates cell proliferation via PDGF-BB and implies there exists a therapeutic potential for impaired neurogenesis induced by Tat and cocaine [44]. …”