Nitric oxide is a chemical messenger implicated in neuronal damage associated with ischemia, neurodegenerative disease, and excitotoxicity. Excitotoxic injury leads to increased NO formation, as well as stimulation of the p38 mitogen-activated protein (MAP) kinase in neurons. In the present study, we determined if NO-induced cell death in neurons was dependent on p38 MAP kinase activity. Sodium nitroprusside (SNP), an NO donor, elevated caspase activity and induced death in human SH-SY5Y neuroblastoma cells and primary cultures of cortical neurons. Concomitant treatment with SB203580, a p38 MAP kinase inhibitor, diminished caspase induction and protected SH-SY5Y cells and primary cultures of cortical neurons from NO-induced cell death, whereas the caspase inhibitor zVAD-fmk did not provide significant protection. A role for p38 MAP kinase was further substantiated by the observation that SB203580 blocked translocation of the cell death activator, Bax, from the cytosol to the mitochondria after treatment with SNP. Moreover, expressing a constitutively active form of MKK3, a direct activator of p38 MAP kinase promoted Bax translocation and cell death in the absence of SNP. Bax-deficient cortical neurons were resistant to SNP, further demonstrating the necessity of Bax in this mode of cell death. These results demonstrate that p38 MAP kinase activity plays a critical role in NO-mediated cell death in neurons by stimulating Bax translocation to the mitochondria, thereby activating the cell death pathway.
Adults and children with low-grade gliomas often present with medically refractory epilepsy. Currently, controversy exists regarding the need for intraoperative electrocorticography (ECoG) to identify and, separately, resect seizure foci versus tumor removal alone to yield maximum seizure control in this patient population. Forty-five patients with low-grade gliomas and intractable epilepsy were retrospectively analyzed with respect to preoperative seizure frequency and duration, number of antiepileptic drugs, intraoperative ECoG data (single versus multiple foci), histology of resected seizure foci, and postoperative control of seizures with or without antiepileptic drugs. Multiple versus single seizure foci were more likely to be associated with a longer preoperative duration of epilepsy. Of the 45 patients studied, 24 were no longer taking antiepileptic drugs and were seizure-free (mean follow-up interval 54 months). Seventeen patients, who all had complete control of their seizures, remained on antiepileptic drugs at lower doses (mean follow-up interval 44 months); seven of these patients were seizure-free postoperatively, yet the referring physician was reluctant to taper the antiepileptic drugs. Four patients continued to have seizures while receiving antiepileptic drugs, although at a reduced frequency and severity. In this series 41% of the adults versus 85% of the children were seizure-free while no longer receiving antiepileptic drugs, with mean postoperative follow-up periods of 50 and 56 months, respectively. This difference was statistically significant (p = 0.016). Therefore, based on this experience and in comparison with numerous retrospective studies involving similar patients, ECoG is advocated, especially in children and in any patient with a long-standing seizure disorder, to maximize seizure control while minimizing or abolishing the need for postoperative antiepileptic drugs.
Caspases play a pivotal role in neuronal cell death during development and after trophic factor withdrawal. However, the mechanisms regulating caspase activity and the role played by caspase activation in response to neuronal injury is poorly understood. The tumor suppressor gene p53 has been implicated in the loss of neuronal viability caused by excitotoxic and DNA damaging agents. In the present study we determined if p53-mediated neuronal cell death required caspase activation. DNA damage increased caspase activity in both cultured embryonic telencephalic and postnatal cortical neurons in a p53-dependent manner. Caspase inhibitors protected embryonic telencephalic neurons, but not postnatal cortical neurons, from DNA damage-induced cell death as measured by direct cell counting and annexin V staining. In marked contrast to the caspase inhibitors, an inhibitor of the DNA repair enzyme, poly(ADP-ribose) polymerase, conferred significant protection from genotoxic and excitotoxic cell death on postnatal cortical neurons but had no effect on embryonic neurons. Glutamate-mediated excitotoxicity in postnatal neurons was not associated with measurable changes in caspase activity, consistent with the failure of caspase inhibitors to prevent cell death under these conditions. Moreover, adenovirus-mediated overexpression of p53 killed embryonic and postnatal neurons without activating caspases. Thus, p53-mediated neuronal cell death may occur via both caspase-dependent and caspase-independent pathways. These results demonstrate that p53 is required for caspase activation in response to some forms of neuronal injury. However, the relative importance of caspase activation in neurons depends on the developmental status of the cell and the specific nature of the death stimulus.
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