Pyrazole Compound 2-MBAPA as a Novel Inhibitor of Microglial Activation and Neurotoxicity in vitro and in vivo

Article type: Research Article

Authors: Hashioka, Sadayuki^a | McLarnon, James G.^b | Ryu, Jae K.^b | Youssef, Amal M.^c | Abd-El-Aziz, Alaa S.^d | Neeland, Edward G.^d | Klegeris, Andis^{e; *}

Affiliations: [a] Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada | [b] Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada | [c] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt | [d] Department of Chemistry, University of British Columbia Okanagan, Kelowna, BC, Canada | [e] Department of Biology, University of British Columbia Okanagan, Kelowna, BC, Canada

Correspondence: [*] Correspondence to: Andis Klegeris, Department of Biology, University of British Columbia Okanagan, 3333 University Way, Kelowna, BC V1V 1V7, Canada. Tel.: +1 250 807 9557; Fax: +1 250 807 8005; E-mail: andis.klegeris@ubc.ca.

Abstract: Pyrazole derivatives are well documented to possess anti-inflammatory activity but their effects on microglial activation are unknown. We determined the efficacy of the novel pyrazole compound 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 compound at a non-toxic concentration 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 compound 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 compound confers neuroprotection by inhibiting microglial activation. Therefore, further studies with 2-MBAPA and novel analogues based on this lead compound are warranted in an effort to develop new pharmacological agents that may be useful for slowing down progression of AD and other neuroinflammatory disorders associated with activated microglia.

Keywords: Amyloid-β peptide (Aβ_1-42), animal model of Alzheimer's disease, microglia, neuroinflammation, neurotoxicity, pyrazole derivatives

DOI: 10.3233/JAD-2011-110698

Journal: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 531-541, 2011