Loss of N-methyl-d-aspartate (NMDA) receptor binding in rat hippocampal areas at the chronic stage after transient forebrain ischemia: Histological and NMDA receptor binding studies

Abstract

Although neuronal death following brain ischemia was originally considered to be due to an energy deficiency resulting from an impaired respiratory chain, the observation of "delayed neuronal death" indicated some other factor. It is believed that delayed neuronal death after transient forebrain ischemia appears as a result of release of glutamate, an excitatory amino acid. In the present study, transient ischemia for 20 minutes in a rat four-vessel occlusion model was induced, and serial changes in histology and N-methyl-D-aspartate receptor (NMDA-R) binding were evaluated up to the chronic stage. Destruction of pyramidal cells and extensive astrocytic proliferation in the CA1 area of the hippocampus was completed by 10 days after cerebral ischemia followed by cerebral blood recirculation. However, the glutamate receptor subtype, NMDA-R, showed no change in all brain regions until after 10 days, but decreased in the hippocampus to 50% after 21 days despite no evidence of histological progression of neuronal death. The results show that the time course for appearance of light microscopic damage in the hippocampal region does not parallel that for depletion of NMDA-R binding sites.

Persistent Region-Dependent Neuroinflammation, Nmda Receptor Loss and Atrophy In An Animal Model of Penetrating Brain Injury

“…These results are similar to those we previously reported in animals treated with intracisternal LPS and killed 7 days later [16]. Region-selective loss of NMDAR was also reported by us and others in animal models of stroke and closed head injury [18,20,34,35]. At the later time points (30 and 60 days postinjury), which were not previously investigated, we noted a delayed bilateral decrease in NMDARs in some regions, although there was no delayed increase in TSPO.…”

Transient focal ischemia results in persistent and widespread neuroinflammation and loss of glutamate NMDA receptors

“…These results, too, are in line with the relevant human stroke literature showing the increased PK11195 signal spreading to remote and contralateral regions in the subacute, rather than acute phase after ischemia (Pappata et al, 2000; Gerhard et al 2000, 2005). Unlike neuroinflammation, the effect of focal ischemia on NMDA receptors has not been investigated in either humans or animal models, although bilateral reductions in NMDAR density and gene expression were documented in the aftermath of global forebrain ischemia (Ogawa et al, 1991; Dalkara et al, 1996; Liu et al, 2007) and traumatic brain injury (Miller et al, 1990; Sihver et al, 2001; Biegon et al, 2004). …”

“…In the vicinity of the lesions as well as in remote non-infarcted regions where no cell loss occurs, most notably the contralateral hemisphere, receptor down regulation and reduced gene expression are likely to occur in response to the high levels of agonist (glutamate) released during ischemia in the terminal fields of damaged or hyper-excited neurons (e.g. Biegon et al, 2004; Ogawa et al, 1991). Another possible mechanism for loss of NMDAR binding is NMDAR internalization in response to amyloid beta release, which was reported in MCAO rats (Li et al, 2009; Snyder et al, 2005).…”

“…Biegon et al, 2002, 2004; Dalkara et al, 1996, Grossman et al, 2003; Izquierdo, 1991; Liu et al, 2007, McGeer et al, 2010. Miller et al, 1990; Ogawa et al, 1991, Penney et al, 1990, Shohami et al, 2003, Sihver et al, 2001). The present study was designed to test the hypothesis that like the above mentioned pathologies, focal ischemia results in persistent loss of NMDAR which is augmented by neuroinflammation and may be relevant to long-term cognitive deficits in stroke victims.…”

Evaluation of neuroprotection and behavioral recovery by the kappa-opioid, PD117302 following transient forebrain ischemia

“…PD117302 has been shown to reduce delayed for 24 h, or more, following the ischemic episode CAI cell loss following ischemia in the gerbil (18). PD117302 (26,32). Considerable evidence suggests that excessive glutahas also been shown to protect against NMDA-induced convulmate-and aspartate-stimulated NMDA activity mediates delayed sions in rats (38), and to reduce glutamate neurotoxicity in vitro neuronal cell death (for reviews, see (3,23,33)].…”