Subtoxic N‐methyl‐D‐aspartate delayed neuronal death in ischemic brain injury through TrkB receptor‐ and calmodulin‐mediated PI‐3K/Akt pathway activation

Abstract

Previous studies have shown that subtoxic NMDA moderated the neuronal survival in vitro and vivo. We performed this experiment to clarify the precise mechanism underlie subtoxic NMDA delayed neuronal death in ischemic brain injury. We found that pretreatment of NMDA (100 mg/kg) increased the number of the surviving CA1 pyramidal cells of hippocampus at 5 days of reperfusion. This dose of NMDA could also enhance Akt activation after ischemia/reperfusion (I/R). Here, we examined the possible mechanism that NMDA induced Akt activation. On the one hand, we found NMDA receptor-mediated Akt activation was associated with increased expression of BDNF (brain-derived neurotrophic factor) and activation of its high-affinity receptor TrkB after I/R in the hippocampus CA1 region, which could be held down by TrkB receptor antagonist K252a. On the other hand, we found that NMDA enhanced the binding of Ca2+-dependent calmodulin (CaM) to p85 (the regulation subunit of PI-3K), which led to the activation of Akt. W-13, an active CaM inhibitor, prevented the combination of CaM and p85 and subsequent Akt activation. Furthermore, NMDA receptor-mediated Akt activation was reversed by combined treatment with LY294002, the specific blockade of PI-3K. Taken together, our results suggested that subtoxic NMDA exerts the neuroprotective effect via activation of prosurvival PI-3K/Akt pathway against ischemic brain injury, and BDNF-TrkB signaling and Ca2+-dependent CaM cascade might contribute to NMDA induced activation of PI-3K/Akt pathway.

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

“…In the HD cell model STHdh Q111/Q111 enhanced NMDAR signaling upregulates Akt activity, 12 and here we show that this also occurs in R6/1 mice striatum as increased pAkt (Ser473) levels were observed after QUIN injection. The activation of Akt through NMDAR stimulation 30 or by oxidative stress 31 is transient, but here we show that increased pAkt (Ser473) levels are maintained through the course of the disease. The levels of pAkt (Ser473) may depend upon a dynamic balance between PHLPP1 levels and Akt-activating mechanisms.…”

“…6 However, here changes in pAkt (Ser473) levels could not be related with endogenous levels of BDNF, although we cannot rule out the possible participation of other trophic factors. Neurons can also activate PI3K in response to NMDAR stimulation 30 or to oxidative stress. 31 Interestingly, these inducers have been shown to participate in HD.…”

Expression of heat shock transcription factors and heat shock protein 72 in rat retina after intravitreal injection of low dose N-methyl-d-aspartate

“…It is known that high concentrations of NMDA cause Ca 2+ overloading in cytoplasm and induce neuronal death in the central nervous system, known as excitotoxicity [26,27]. Interestingly, low (non-lethal) doses of NMDA are neuroprotective against subsequent damage in neuronal cultures [23][24][25] and in cerebral ischemia models [28]. This neuroprotective effect is called "NMDA-preconditioning".…”

“…Interestingly, low (non-lethal) doses of NMDA are neuroprotective against subsequent damage in neuronal cultures [23][24][25] and in cerebral ischemia models [28]. This neuroprotective effect is called "NMDA-preconditioning".…”

Protective effect of Shenqi-wan and its fractions on N-methyl-D-aspartate-induced excitotoxicity in rat hippocampus

“…Because NMDA receptors play a crucial role in glutamateinduced acute neuronal damage, NMDA receptor antagonists are thought to reduce neuronal cell death during and following ischemic attacks (Simon et al, 1984). Kim et al (2007) showed the activation of protein kinase C through cyclooxygnase-2 (COX-2) pathway inducted neuroprotective effect on NMDA-induced ischemia, and Xu et al (2007) suggested that NMDA receptors activated prosuvival pathway.…”