Page 268 - Read Online

Page 4 of 11 Vasefi et al. Vessel Plus 2020;4:24 I http://dx.doi.org/10.20517/2574-1209.2020.16
[32]
Valenzuela et al. electrophysiological studies were the first to reveal the inhibitory effect of PDGF on
NMDA receptors. Brief activation of PDGF receptors by PDGF-BB can trigger long-lasting inhibition on
NMDA receptors in rat hippocampal slices, cultured hippocampal neurons, and Xenopus oocytes [32,33] . The
2+
mechanism of this inhibition involves PLC -induced elevation of intracellular Ca and protein phosphatase
γ
[33]
2+
activity downstream of Ca signaling to modulate the NMDA receptor function . Follow-up studies
determined that PDGFb receptor signaling selectively inhibits NR2B-containing NMDA receptors and
[7]
decreases surface localization of NR2B subunits . Abelson tyrosine kinase activated downstream of
PDGFb receptors or added directly (intracellularly) to hippocampal neurons similarly inhibits NMDA
[34]
receptor signaling . In addition to the inhibition of NMDA receptor signaling, PDGF-BB also reduces
oxidative stress and calpain activation induced by hydrogen peroxide via reduction in intracellular calcium
and via the PI3 kinase signaling pathway [35,36] .
Excess glutamatergic signaling, and subsequent over-activation of NMDA receptors, is one of the signaling
events associated with neurotoxicity after stroke. Tseng and colleagues directly examined the neuroprotective
effect of PDGF-BB against glutamate- or NMDA-induced excitotoxicity in cultured hippocampal neurons
and found that PDGF-BB pretreatment can protect neurons from these insults in both dose- and time-
[37]
[37]
dependent manners . Pretreatment with 10 ng/ml of PDGF-BB for 24 h is required for maximal effect ,
although as little as 10 min of PDGF-BB pretreatment is sufficient to protect neurons from NMDA
[7]
receptor-induced toxicity, if applied immediately prior to the insult . Besides the direct inhibition of the
NMDA receptor, PDGF-associated neuroprotective effects against excitotoxicity are also attributed to its
ability to increase glutamate reuptake by modulating the activity of the glutamate transporter, EAAC1.
Sims and colleagues found that PDGF can increase the activity and surface expression of EAAC1 and these
[38]
[39]
effects depend on the activation of PI3 kinase and the activation of Akt .
In vivo, pretreatment with PDGF-BB, but not AA, two days before forebrain ischemia in rats protects CA1
[40]
pyramidal neurons from delayed neuronal death on day 7 after ischemia in a dose-dependent manner .
Continuous infusion of PDGF-BB for 7 days into the cerebral ventricles of gerbils with transient forebrain
ischemia improves their performance on a passive avoidance task and subsequent histological examinations
[41]
revealed that PDGF-BB increases neuronal survival and the number of remaining synapses .
Administration of PDGF-BB into the left neocortex of Sprague-Dawley rats for 7 or 14 days before ischemia
[42]
decreases the neocortical infarction with the size of infarction the smallest in the 14-day group . Egawa-
Tsuzuki and colleagues found that PDGF-B infusion before and after NMDA injection reduces the size of
[43]
lesions in young rats when their endogenous expression of PDGF-B in neurons is low .

Clearly, the application of PDGF ligands preceding a controlled insult is neuroprotective, but likely not
a feasible therapeutic approach in humans where the insult is not typically predictable. Interestingly,
PDGF signaling may be used as an endogenous neuroprotective response by the CNS after the damage
has already occurred. For example, focal ischemia in rat brains causes a rapid increase in PDGF-B chain

[44]

isoform mRNA transcripts that peaks at 24 h (a similar upregulation of PDGF-B occurs in myocardial
[45]
tissue after ischemia ). PDGF-BB expression is also increased after ischemic preconditioning in the gerbil
[47]
[46]

hippocampus . PDGFb receptor expression rises rapidly after ischemia in the rat brain . Furthermore,
the expression of PDGF-A and PDGF-B mRNA and PDGF-BB and PDGF-AB dimer protein expression
[48]
rises in neurons and supports cells surrounding areas damaged by ischemic events in humans . In
addition, mice without the PDGFb receptor gene are vulnerable to NMDA receptor-induced excitotoxicity
[49]
in terms of increased cell death and lesion size . There is a considerable amount of evidence that
activation of the PDGF system prior to these neuronal insults is neuroprotective and that these insults also
upregulate PDGF system components.