Page 267 - Read Online

Vasefi et al. Vessel Plus 2020;4:24 I http://dx.doi.org/10.20517/2574-1209.2020.16 Page 3 of 11
[15]
chronic one has resulted in an increase in the prevalence of HAND . Despite their effectiveness in the
periphery, limited penetration of antiretroviral therapies into the CNS also contributes to adverse neuronal
[16]
consequences . Although the virus does not infect neurons directly, the viral proteins released from
infected perivascular macrophages and microglia in the CNS can interact with neurons and cause neuronal
[17]
damage and loss . Several growth factors, such as brain-derived growth factor (BDNF) and fibroblast
growth factor (FGF), as well as PDGF-BB, have demonstrated neuroprotective effects against HIV protein
toxicity [18-20] .

Down-regulation of the PDGF-B chain at both the mRNA and protein level is observed in neuroblastoma
SH-SY5Y cell cultures treated with gp120, an HIV envelope glycoprotein, and this protein exerts
neurotoxic effects on SH-SY5Y cells, including increased cell death and loss of neurites [21,22] . These toxic
effects are attenuated by pretreating the cells with PDGF-BB prior to incubation with gp120 in both
SH-SY5Y cells and rat cortical neurons [21,22] . The neuroprotective effects appear to be associated with a
reduction in apoptosis, as measured by reduced gp120-mediated activation of caspase-3 and increased
[21]
Bcl-xL/Bax ratio . Peng and colleagues identified several effectors downstream of PI3K/Akt required for
[22]
neuroprotective effects . GSK-3b inactivation leads to nuclear translocation of b-catenin and NF-κB,
[22]
transcription factors that are involved in cell proliferation and differentiation . Additional potential
neuroprotective mechanisms include phosphorylation of Bad, downregulation of the pro-apoptotic protein,
[22]
Bax, and the inhibition of gp120-induced release of mitochondrial cytochrome C .
PDGF is also neuroprotective against toxicity induced by another HIV-1 protein, Tat [20,23] . PDGF-BB
activation of the PDGFb receptor increases dendrite length and cell viability (via an anti-apoptotic effect)
[23]
in rat primary midbrain neurons exposed to Tat . PDGF-BB also reduces reactive oxygen species (ROS)
production and caspase-3 activation and these effects involve the regulation of ion channels, specifically,
[24]
TRPC subtypes TRPC 5 and TRPC 6, and calcium influx . The PDGF-mediated neuroprotection
against Tat via TRPC is also confirmed in vivo: PDGF is able to protect dopaminergic neurons in adult
[23]
[25]
mice injected with HIV-1 Tat and TRPC activity contributes to the protection . Zhu et al. examined
the PDGF-mediated neuroprotection against Tat in differentiated SH-SY5Y cells and observed the same
neuroprotective effect observed by Yao in rat primary neurons and the neuroprotective effect also involves
2+
2+
elevation of intracellular Ca and requires Ca influx. N-methyl-D-aspartate (NMDA) receptors may
also be involved, as the NMDA receptor antagonist MK-801 is able to abolish Tat-induced toxicity in
differentiated SH-SY5Y cells .
[25]
[26]
In addition to direct neuronal toxicity, HIV proteins can impair neurogenesis in the hippocampus . The
[27]
PDGF system is important for neurogenesis, both in the developing and mature CNS . PDGF-BB can
increase the number of neural progenitor cells (NPC) in the rat hippocampus in the presence of Tat [26,28]
as well as after cocaine administration [26,29] . Similar to the previous findings by the Buch group, a role
for p38, JNK, MAPK, and GSK3b and for the TRPC channel and calcium signaling are involved in this
[24]
neuroprotective pathway . Knocking-down PDGFb receptor expression reduces neurogenesis after middle
cerebral artery occlusion in mice, further suggesting a crucial role for PDGF-associated neurogenesis after
[30]
neuronal injury .

While many of the neuroprotective effects exerted by the PDGF system appear to be due to PDGF-BB,
other ligands also exert protective effects. For example, PDGF-CC is also protective against Tat via similar
[31]
downstream signaling pathways (PI3K/Akt/TRPC) as PDGF-BB and PDGF-CC was recently shown to
reverse synaptic changes caused by Tat .
[31]
STROKE AND ISCHEMIA
One of the major areas of PDGF neuroprotection studies has been focused on the direct inhibitory effect of
PDGF on NMDA receptors and the associated neuroprotection against NMDA receptor-induced toxicity.