Biochemistry & Pharmacology: Open Access
Open Access

Abstract

Matrix Metalloproteinase-9 Triggers the Gap Junction Impairment and Somatosensory Neuronal Dysfunction in Septic Encephalopathy

Huan Wang, Yukio Imamura, Naoya Matsumoto, Nao Yoshikawa, Junichiro Nakagawa, Kazuma Yamakawa, Tomoki Yamada, Yuki Murakami, Satoko Mitani, Takashi Jin, Hiroshi Ogura, Takeshi Shimazu and Akitoshi Seiyama

Although septic encephalopathy leads to be the devastating neurological symptoms including sensory dysfunction, cognitive impairment and unconsciousness, potent substrates and their effects inducing the synaptic dysfunction remain obscure. In this study, we successfully characterized the sensory dysfunction with immunohistochemistry, immunoblotting and electrophysiology. A mouse model of septic encephalopathy was examined at 20 hrs after cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (1 mg). We found several effects of active enzyme of matrix metalloproteinases-9 (active MMP-9) on the somatosensory cortex, thalamus and prefrontal cortex related to the sensory functions in septic encephalopathy. At first, active MMP-9 was up-regulated. Second, both of the occludin, tight junction protein composing blood brain barrier, and the connexin-43, transmembrane protein of gap junction, which were potent substrate of active MMP-9, were disrupted. Third, the evoked local field potentials in cortical and thalamic neurons were impeded during sensory neuronal stimulation. Conversely, matrix metalloproteinase inhibitor GM6001 significantly protected the reduction of occludin, connexin-43 and the regression of neuronal activities. In conclusion, MMP-9 is a prerequisite candidate for protection of the junction proteins reduction and for the potent therapeutics in the sensory dysfunction in septic encephalopathy.