Hepatocyte growth factor (HGF) attenuates gliosis and motoneuronal degeneration in the brainstem motor nuclei of a transgenic mouse model of ALS.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of brainstem and spinal motoneurons. Although prevention of motoneuronal degeneration has been postulated as the primary target for a cure, accumulating evidence suggests that microglial accumulation contributes to disease progression. This study was designed to assess the ability of HGF to modulate microglial accumulation and motoneuronal degeneration in brainstem motor nuclei, using double transgenic mice overexpressing mutated SOD1(G93A) and HGF (G93A/HGF). Histological and immunohistochemical analyses of the tissues of G93A/HGF mice revealed a marked decrease in the number of microglia and reactive astrocytes and an attenuation of the loss of motoneurons in facial and hypoglossal nuclei compared with G93A mice. HGF overexpression attenuated monocyte chemoattractant protein-1 (MCP-1) induction, predominantly in astrocytes; suppressed activation of caspase-1, -3 and -9; and, increased X chromosome-linked inhibition of apoptosis protein (XIAP) in the motoneurons of G93A mice. The implication is that HGF reduces microglial accumulation by suppressing MCP-1 induction and prevents motoneuronal death through inhibition of pro-apoptotic protein activation. These findings suggest that, in addition to direct neurotrophic activity on motoneurons, HGF-suppression of gliosis may retard disease progression, making HGF a potential therapeutic agent for the treatment of ALS patients.
Kadoyama
Keiichi
K
Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, Osaka, Japan.
Funakoshi
Hiroshi
H
Ohya
Wakana
W
Nakamura
Toshikazu
T
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001933:Brain Stem / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000187:drug effects / Q000378:metabolism; D003391:Cranial Nerves / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D017228:Hepatocyte Growth Factor / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D016896:Treatment Outcome
D051017:Apoptosis Regulatory Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018696:Neuroprotective Agents; C000606290:SOD1 protein, human; D017228:Hepatocyte Growth Factor; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1