The c-Jun N-terminal kinase (JNK) undergoes complete inactivation following the 
intense activation induced by cerebral ischemia and reperfusion in rat 
hippocampi. This study examines the molecular mechanism underlying JNK 
dephosphorylation and inactivation evoked by dual-specificity phosphates 
following cerebral ischemia. The results revealed upregulation of 
dual-specificity phosphatase M3/6 (DUSP8) activity at 4 h of reperfusion in rat 
hippocampi. This was accompanied by the dephosphorylation of JNK. The M3/6 
inhibitor, anisomycin, was found to enhance JNK activity following postischemic 
reperfusion, suggesting that M3/6 is closely associated with JNK inactivation 
following cerebral ischemia. Cerebral ischemia also induced an increase in heat 
shock protein (HSP70) levels, which is involved in the upregulation of soluble 
cytoplasmic M3/6 levels. The inhibition of HSP70 using quercetin resulted in an 
elevation of JNK activity by decreasing the cytoplasmic solubility of M3/6. The 
findings of the current study suggest that M3/6 is implicated in the 
inactivation of JNK in response to cerebral ischemia, which requires the 
molecular chaperone HSP70 to facilitate the correction of folding defects.