Pyrazole compound 2-MBAPA as a novel inhibitor of microglial activation and neurotoxicity in vitro and in vivo

Pyrazole derivs. are well documented to possess anti-inflammatory activity but their effects on microglial activation are unknown. We detd. the efficacy of the novel pyrazole compd. 2-MBAPA (R/S-(±)-2-Methylbenzylamino 2-oxo-N-[4-cyano-1-phenyl-1H-pyrazol-5-yl] acetamide) on activated microglia under conditions relevant to inflammation in Alzheimer's disease (AD) brain. The compd. at a non-toxic concn. inhibited secretion of tumor necrosis factor (TNF)-α by activated human microglia and attenuated toxicity of conditioned medium from activated human microglia towards human SH-SY5Y neuroblastoma cells in vitro. The 2-MBAPA neuroprotection was further demonstrated in vivo using an animal model of AD. The compd. inhibited microgliosis, but not astrogliosis, in amyloid-β peptide (Aβ)1-42-injected rat brain. 2-MBAPA also diminished neuronal loss in the dentate gyrus caused by Aβ1-42 injection. These results indicate that this novel pyrazole compd. confers neuroprotection by inhibiting microglial activation. Therefore, further studies with 2-MBAPA and novel analogs based on this lead compd. are warranted in an effort to develop new pharmacol. agents that may be useful for slowing down progression of AD and other neuroinflammatory disorders assocd. with activated microglia. [on SciFinder(R)]