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PDGF-A, -B, -C, and -D that can either homo- or hetero-dimerize into PDGF-AB, -AA, -BB, -CC, and
[2]
[1]
-DD . The PDGF ligands act through PDGF α and b receptors and both are necessary for normal
[2]
physiological development . Upon binding PDGF, receptors dimerize and the tyrosine kinase domains
transautophosphorylate one another on multiple tyrosine residues. Effectors such as phospholipase C (PLC)
γ, phosphatidylinositol 3-kinase (PI3-kinase), Src family tyrosine kinases, tyrosine phosphatases such as
SHP-2, and a GTPase-activating protein for Ras are activated after phosphorylation of the PDGF receptor .
[3]
Thus, by direct activation of effector proteins or via cytoplasmic adaptor proteins, PDGF receptors initiate a
wide variety of downstream signaling pathways.

[4]
PDGF and its receptors are widely expressed throughout the central nervous system (CNS) and are
[5]
involved in neuronal growth and differentiation although their physiological role in mature neurons
is not yet fully characterized. PDGFb receptors are found in pyramidal neurons in the hippocampus
[6,7]
[8]
whereas the PDGFα receptor and its primary ligand, PDGF-AA, are found in both neuronal and non-
[9]
neuronal cells. Herein, we will briefly review the direct and indirect [i.e., GPRC - receptor tyrosine kinase
(RTK) transactivation] neuroprotective effects of PDGF receptor signaling, with a focus on the PDGFb
receptors. Sil and colleagues have recently reviewed the PDGF system in the central nervous system and
provided a comprehensive and detailed description of PDGF expression and signaling in CNS cell types
including neurons, astrocytes, microglia, oligodendrocytes, signaling in the spinal cord, and the role of the
[4]
PDGF system in the blood-brain-barrier .

THERAPEUTIC APPROACHES TO MODULATING PDGF SIGNALING
Several approaches to target PDGF signaling have been proposed or evaluated, and many hold promise
despite technical, logistical, and therapeutic challenges. As large growth factors, PDGF ligands are
classified as biologics and would require parenteral administration. Even so, they are too large to cross
the blood-brain barrier and enter the CNS, thus would require intrathecal administration directly into
[10]
the cerebrospinal fluid, or direct injection into the brain, such as intracerebroventricular injection .
An alternative approach, discussed below, could be to indirectly transactivate PDGF receptors after the
activation of G protein-coupled receptors (GPCRs). On the other hand, approaches to inhibit PDGF
receptor signaling include antibodies that target PDGF ligands or receptors, small molecule inhibitors of
PDGF receptor kinase activity, genetic manipulations, or targeting specific downstream signaling pathways
at the receptor level . Papadopolous and Lennartsson recently reviewed the approaches to inhibit PDGF
[2]
signaling in cancer therapies and provided a detailed description of current and future therapies that target
[11]
the PDGF system . Indeed, beyond the neuroprotective roles discussed here, the PDGF system holds
the potential to better understand and perhaps treat several non-neuronal disease states including cancer,
[12]
fibrosis/connective tissue disorders, and vascular disease .

HUMAN IMMUNODEFICIENCY VIRUS - ASSOCIATED NEUROCOGNITIVE DISORDER
Although specific dementias have distinct pathologies, disease courses, and outcomes, all include neuronal
dysfunction, and many include disruptions in neurotransmitter homeostasis and signaling. Alterations in
glutamate homeostasis in particular, including excitotoxicity, contributes to the pathology of ischemia and
[13]
several neurodegenerative diseases . As dementias progress, accumulation of toxic proteins or aggregates,
coupled with neuronal dysfunction and inflammation, reduce neuronal cell viability. Thus, there is a
significant interest in the role of neuroprotective signaling pathways to treat these conditions.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are neurocognitive
complications resulting from HIV infection and are classified as: asymptomatic neurocognitive impairment,
[14]
mild cognitive motor disorder and HIV-associated dementia (HAD), in order of severity . As the efficacy
of antiretroviral therapies has improved, the transformation of HIV-infection from a fatal disease to a