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Neuronal cell death due to glutamate excitotocity is mediated by p38 activation in the rat cerebral cortex
J E Segura Torres1, V Chaparro-Huerta, M C Rivera Cervantres
1Laboratorio de Neurobiología Celular and Molecular, División de Neurociencias, CIBO, Instituto Mexicano del Seguro Social, Apdo. Postal #4-160, Guadalajara, Jalisco 44421, Mexico.
Abstract:
Excitotoxic neuronal death occurs through the activation of NMDA and non-NMDA glutamatergic receptors in the CNS. Glutamate also induces strong activation of p38 and indeed, cell death can be prevented by inhibitors of the p38 pathway. Furthermore, intracellular signals generated by AMPA receptors activate the stress sensitive MAP kinases implicated in apoptotic neuronal death, such as JNK and p38. To investigate the relationship between these elements, we have used immunohistochemistry to analyze the expression of GluR2 in the cerebral cortex of postnatal rats (postnatal Day [PD] 8 and 14) after administering them with monosodium glutamate (MSG; 4 mg/g body weight on PD1, 3, 5, and 7). Similarly, the expression of REST, Fas-L and Bcl-2 mRNA transcripts in animals exposed to a p38 inhibitor, SB203580 (0.42 microg/g body weight, administered subcutaneously) was determined by reverse transcriptase-PCR. The enhanced GluR2-expression in the cerebral cortex at PD8 and the down regulation of this receptor at PD14 was correlated with neuronal damage induced by excitotoxicity. In addition, the enhanced expression of REST at PD8 and PD14 suggests that the induction of REST transcription contributes to glutamate-induced excitotoxic neurodegeneration, possibly by modulating GluR2 expression. Fas-L and Bcl-2 over expression at PD8 and their subsequent down regulation at PD14 also suggests that Fas-L could be the direct effector of apoptosis in the cerebral cortex. On the other hand, the presence of Bcl-2 at PD8 could attenuate certain survival signals in neurons under these neurotoxic conditions. Thus, a change in glutamate receptor composition, and enhanced Fas-L and Bcl-2 expression, coupled with activation of the p38/SAPK pathway appear to be events involved in the neuronal apoptosis induced under neurotoxic conditions.
Insights
Excitotoxicity causes neuronal death via glutamate receptors and p38 activation. Inhibiting p38 and altering glutamate receptor expression may prevent this, suggesting new therapeutic targets for neurodegeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Excitotoxic neuronal death is mediated by NMDA and non-NMDA glutamate receptors.
- Glutamate receptor activation triggers stress-sensitive MAP kinases, including p38 and JNK, implicated in apoptosis.
- The p38 pathway is a key target for preventing excitotoxic neuronal death.
Purpose of the Study:
- To investigate the relationship between glutamate receptors, p38 pathway activation, and excitotoxic neurodegeneration.
- To analyze the expression of GluR2, REST, Fas-L, and Bcl-2 in response to monosodium glutamate (MSG) and p38 inhibition.
- To elucidate the molecular mechanisms underlying glutamate-induced excitotoxic neuronal death.
Main Methods:
- Immunohistochemistry was used to assess GluR2 expression in postnatal rat cerebral cortex.
- Reverse transcriptase-PCR determined REST, Fas-L, and Bcl-2 mRNA transcripts in rats treated with a p38 inhibitor (SB203580).
- Monosodium glutamate (MSG) was administered to induce excitotoxicity; p38 inhibitor SB203580 was used to block p38 pathway activation.
Main Results:
- Enhanced GluR2 expression at postnatal Day 8 (PD8) and downregulation at PD14 correlated with excitotoxic neuronal damage.
- Increased REST expression at PD8 and PD14 suggests its role in modulating GluR2 expression during excitotoxicity.
- Fas-L and Bcl-2 overexpression at PD8 followed by downregulation at PD14 indicates Fas-L as a potential apoptosis effector, while Bcl-2 may offer transient neuroprotection.
Conclusions:
- Changes in glutamate receptor composition, particularly GluR2, are linked to excitotoxic neurodegeneration.
- REST transcription induction contributes to glutamate-induced neurodegeneration, potentially by affecting GluR2.
- Fas-L and Bcl-2 dynamics, alongside p38/SAPK pathway activation, are critical events in neurotoxic conditions leading to neuronal apoptosis.
