Aims: 

Intraventricular (icv) injection of kainate (KA) causes an acute excitotoxic lesion to hippocampal CA3 region. NMDA was shown to protect neurons against in vitro/in vivo induced cell death. We used in vivo approach to study NMDA or AMPA preconditioning of KA–induced neurodegeneration.

Methods: 

Preconditioning injections (icv) of NMDA or AMPA (with cyclothiazide) to anesthetized rats (urethane, 1.5 g/kg) were followed by KA (0.15 mg, icv). Light and electron microscopy enabled to evaluate neurodegeneration. c-Fos or Hsp70 immunohistochemistry (IHC) was used to estimate neuronal activation/severe cellular stress, respectively. Quantitative evaluation of morphology and IHC data were complemented by ANOVA with post-hoc analysis of significant differences.

Results: 

KA alone depressed c-Fos induction in CA3a already by one hr post injection (-69%, CA3a vs. CA3b, p <= 0.01), causing neurodegeneration with necrotic and apoptotic signs. On the contrary, c-Fos induced by NMDA injection, which preceded KA by one hour, was still elevated in CA3a at 1 hr (+169%) and 2 hrs after KA (+114%, both p <= 0.01). The onset of neuronal degeneration was delayed in similar way indicating transient neuroprotection. However, c-Fos and neurons of CA3a deteriorated by 4 hrs to the same level as those seen after KA alone. NMDA-induced c-Fos expression was completely blocked by MK-801. However, preconditioning with AMPA failed to show any preventive effect. In addition, none of the above treatments induced Hsp70.

Conclusion: 

Enhancing synaptic activity of neurons through NMDA specific signalling might be the way to rescue neurons suffering from excitotoxicity in the ischemic or injured brain.

Supported by College of Graduate Studies Grant to S.M.