Pituitary Adenylate Cyclase Activating Polypeptide Elicits Neuroprotection Against Acute Ischemic Neuronal Cell Death Associated with NMDA Receptors

Abstract

Background/Aims: The endogenous neurotrophic peptides pituitary adenylate cyclase-activating polypeptides (PACAP-27/38) protect against stroke, but the molecular mechanism remains unknown. Methods: Primary rat neural cells were exposed to PACAP-27 or PACAP-38 before induction of experimental acute ischemic stroke via oxygen-glucose deprivation-reperfusion (OGD/R) injury. To reveal PACAP’s role in neuroprotection, we employed fluorescent live/dead cell viability and caspase 3 assays, optical densitometry of mitochondrial dehydrogenase and cell growth, glutathione disulfide luciferase activity, ELISA for high mobility group box1 extracellular concentration, ATP bioluminescence, Western blot analysis of PACAP, NMDA subunits, apoptosis regulator Bcl-2, social interaction hormone oxytocin, and trophic factor BDNF, and immunocytochemical analysis of PACAP. Results: Both PACAP-27 and PACAP-38 (PACAP-27/38) increased cell viability, decreased oxidative stress-induced cell damage, maintained mitochondrial activity, prevented the release of high mobility group box1, and reduced cytochrome c/caspase 3-induced apoptosis. PACAP-27/38 increased the protein expression levels of BDNF, Bcl-2, oxytocin, and precursor PACAP. N-methyl-D-aspartate receptor (NMDAR)-induced excitotoxicity contributes to the cell death associated with stroke. PACAP-27/38 modulated the protein expression levels of NMDAR subunits. PACAP-27/38 increased the protein expression levels of the GluN1 subunit, and decreased that of the GluN2B and GluN2D subunits. PACAP-27, but not PACAP-38, increased the expression level of the GluN2C subunit. Conclusion: This study provides evidence that PACAP regulated NMDAR subunits, affording neuroprotection after OGD/R injury.

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“…Not surprisingly, then, in vitro and animal models suggest that PACAP elicits similar neuroprotective processes . These include antiapoptotic signaling, production of BDNF and nitric oxide, adult neurogenesis, and antioxidant defenses . PACAP may confer resistance to excitotoxicity by facilitating the uptake of glutamate by astrocytes, and by changing the configuration of NMDA receptors .…”

“…These include antiapoptotic signaling, production of BDNF and nitric oxide, adult neurogenesis, and antioxidant defenses . PACAP may confer resistance to excitotoxicity by facilitating the uptake of glutamate by astrocytes, and by changing the configuration of NMDA receptors . PACAP appears to strengthen the BBB under conditions of glucose deprivation and oxidative stress and it facilitates angiogenesis and capillary formation by cerebral microvessel endothelial cells .…”

Modeling rapid and selective capture of nNOS–PSD-95 uncouplers from Sanhuang Xiexin decoction by novel molecularly imprinted polymers based on metal–organic frameworks

“…1,2 Under the condition of cerebral ischemia, excitatory amino acids are released excessively, causing the over-activation of N-methyl-D-aspartate receptor (NMDAR) and the excitation of neuronal nitric oxide synthase (nNOS), which nally results in the over-release of nitric oxide (NO), apoptosis, and nerve damage. 3,4 It was found that blocking the coupling of postsynaptic density protein-95 (PSD-95) and nNOS, downstream of the NMDAR-PSD-95-nNOS signaling pathway, can inhibit the pathological release of NO caused by cerebral ischemia and then cure ischemic stroke without affecting the physiological functions of NMDAR and nNOS. [5][6][7] and ZL006, 9 small molecule inhibitors of the nNOS-PSD-95 interaction, were developed and reported to have potent neuroprotective activity both in vivo and in vitro.…”

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“…The NMDAR functions in a series of heterotetrameric assemblies that typically associate two GluN1 subunits with the same two GluN2 subunits, or a mixture of GluN2 (for example, 2GluN1/2GluN2A or 2GluN1/GluN2A/GluN2B). NMDARs are principally tetrameric assemblies of two obligatory, glycine-binding GluN1 subunits, and two glutamate-binding GluN2A/B subunits [22,23]. Equilibrium shift of NMDAR subunit expression pattern is a key control point for determination of receptor diversity of the plasma membrane [23].…”

“…NMDARs are principally tetrameric assemblies of two obligatory, glycine-binding GluN1 subunits, and two glutamate-binding GluN2A/B subunits [22,23]. Equilibrium shift of NMDAR subunit expression pattern is a key control point for determination of receptor diversity of the plasma membrane [23].…”