Involvement of MAPK pathways in NMDA-induced apoptosis of rat cortical neurons.

NMDA-induced excitotoxicity cause severe neuronal damage including apoptosis and necrosis. The present study was aimed to evaluate the proportion of NMDA-induced apoptosis of rat cortical neurons and discover signal transduction mechanism. Caspase inhibitor and lactate dehydrogenase (LDH) assay were used to study the NMDA-induced apoptosis. To explore the involved signal pathways, the primary culture of rat cortical neurons were pretreated by the inhibitors of three MAPK pathways, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. With 2 h of NMDA treatment, cellular apoptosis was measured by caspase-3 activity, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) and Annexin V staining. The results showed that: (1) Caspase-dependent apoptosis accounted for 22.49% in NMDA-induced neuronal death; (2) Pretreatment with p38 MAPK inhibitor SB203580 (10 µmol/L) significantly decreased NMDA-mediated caspase-3 activity by 30.43% (P < 0.05). However, ERK inhibitor PD98059 (20 µmol/L) or JNK inhibitor SP600125 (20 µmol/L) did not influence caspase-3 activity; (3) Pretreatment with SB203580 significantly reduced the number of NMDA-induced TUNEL-positive cells by 33.10% (P < 0.05). PD98059 (20 µmol/L) or SP600125 (20 µmol/L) did not show obvious effect; (4) Pretreatment with SB203580 (10 µmol/L) significantly reduced the number of NMDA-induced early apoptotic neurons by 55.56% (P < 0.05). Also, SP600125 (20 µmol/L) significantly decreased the amount of late apoptotic/dead cells by 67.59% (P < 0.05). There was no effect of PD98059 (20 µmol/L). These results indicate that: (1) NMDA induces neuronal apoptosis besides necrosis; (2) p38 MAPK, but not JNK and ERK, is involved in NMDA-induced neuronal apoptosis, and inhibition of the apoptotic signaling pathway contributes to neuroprotection; (3) JNK activation might contribute to NMDA-induced neuronal necrosis rather than apoptosis.

[Neuroprotective role of silent information regulator 1 in Alzheimer's disease].

Silent information regulator 1 (SIRT1), an NAD(+)-dependent deacetylase, is involved in the regulation of gene transcription, energy metabolism and cell aging. Recent studies have showed that SIRT1 possesses neuroprotective effects, however, it is not very clear how SIRT1 exerts the neuroprotection in Alzheimer's disease (AD). In this review, we summarized the neuroprotective role of SIRT1 in AD and its possible molecular mechanisms, proposing a novel strategy for preventing and treating neurodegeneration.

Effect of profound hypothermia on genomics of hippocampus following complete cerebral ischemia in rats.

OBJECTIVE: To determine differential gene expression of hippocampus in rats following complete cerebral ischemia with treatment of profound hypothermia compared to normothermia. METHODS: Six rats got 5 minutes of complete cerebral ischemia with circulatory arrest and randomly divided into two groups: normothermia ischemia group (37 +/- 0.3 degrees C, n = 3) and profound hypothermia ischemia group (18 +/- 0.5 degrees C, n = 3). Affymetrix U34A rat arrays were applied to detect the difference of gene expression profile in hippocampus between the two groups. RESULTS: Expression profiles of a total of 75 transcripts in the profound hypothermia ischemia group were statistically different from those of the normothermia ischemia group, and 33 of them were significantly up-regulated and other 42 were significantly down-regulated (p < 0.07). CONCLUSIONS: Compared with normothermia, profound hypothermia had a significant effect on the gene expression profiles following complete cerebral ischemia, which may be involved in the mechanisms of cerebral protection by profound hypothermia.