The Effect of PSD-93 Deficiency on the Expression of Early Inflammatory Cytokines Induced by Ischemic Brain Injury

Abstract

The aim of the study was to explore the effect of PSD-93 deficiency on the expression of early inflammatory cytokines induced by cerebral ischemia/reperfusion injury. Ten-to twelve-week-old male PSD-93 knockout (PSD-93 KO) mice (C57BL/6 genetic background) and wild-type (WT) littermates were randomly divided into sham and ischemia/reperfusion (I/R) group. The focal cerebral I/R model was established by middle cerebral artery occlusion (MCAO) suture method. RT-PCR was used to detect the mRNA expression of IL-6, IL-10, Cox-2, iNOS, and TNFa4h following reperfusion. Infarct volume at different time points after I/R was analyzed using 2,3,5-triphenyl tetrazolium staining, and neurological damage score (neurological severity scores, NSS) was used to evaluate the effect of PSD-93 gene knockout on the MCAO-induced neurological injury. In WT mice, early I/R injury led to the increase in the mRNA expression of proinflammatory cytokines IL-6, Cox-2, iNOS, and TNF-a that coincided with the decrease in the expression of anti-inflammatory cytokine IL-10, as compared to the sham group (P \ 0.05). This effect was markedly attenuated by depleting PSD-93 levels by gene knockout. As compared to sham group, in PSD-93 KO mice I/R4h led to downregulation of Cox-2 and iNOS expression, and increase in the mRNA levels of IL-10 (P \ 0.05). In addition, following MCAO, PSD-93 KO mice exhibited improved NSS and reduced infarct volumes, as compared with WT animals. PSD-93 knockout may play a neuroprotective role by mediating the early release of inflammatory cytokines induced by cerebral ischemia.

PSD-93 mediates the crosstalk between neuron and microglia and facilitates acute ischemic stroke injury by binding to CX3CL1

“…PSD-93 is a scaffold protein in the postsynaptic membrane that mediates the release of inflammatory factors in the early stage of cerebral ischemia through NMDA receptors [16] . In addition, PSD-93 can interact with other proteins with its function structure domain and change the structure and function of other proteins [25][26] .…”

“…Christopherson et al [27] showed that PSD-95, NMDAR and nNOS can assemble into a macromolecular signal complex, and disrupting ischemia-induced interaction of nNOS with PSD-95 improved regenerative repair after stroke [28][29][30] . In addition, PSD-93 can bind to NR2A and nNOS and facilitate ischemic brain injury [16,31] . On the other hand, neuronal excitatory toxicity interacted with microglia-induced inflammatory response in ischemic brain injury [32][33] .…”

“…PSD-93 binds directly to the carboxyl terminus of N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B via the PDZ domain and transports it to the postsynaptic membrane as a major regulator of synaptic maturation [15] . Our recent study showed that the loss of PSD-93 inhibited pro-inflammatory factors and promoted the expression of anti-inflammatory factors, while the application of NMDA receptor (NMDAR) inhibitors provided brain protection [16] . These results suggest that PSD-93 promotes a series of responses to cerebral ischemia-reperfusion injury through the activation of NMDAR, including the regulation of inflammatory factor release in early ischemic cells.…”

PSD-93 Mediates the Crosstalk between Neuron and Microglia and Facilitates Acute Ischemic Stroke Injury by Binding to CX3CL1

“…PSD-93 is a scaffold protein in the postsynaptic membrane that mediates the release of in ammatory factors in the early stage of cerebral ischemia through NMDA receptors [16] . In addition, PSD-93 can interact with other proteins with its function structure domain and change the structure and function of other proteins [25][26] .…”

“…PSD-93 binds directly to the carboxyl terminus of N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B via the PDZ domain and transports it to the postsynaptic membrane as a major regulator of synaptic maturation [15] . Our recent study showed that the loss of PSD-93 inhibited pro-in ammatory factors and promoted the expression of antiin ammatory factors, while the application of NMDA receptor (NMDAR) inhibitors provided brain protection [16] . These results suggest that PSD-93 promotes a series of responses to cerebral ischemiareperfusion injury through the activation of NMDAR, including the regulation of in ammatory factor release in early ischemic cells.…”