Analysis of neurotrophic effects of hepatocyte growth factor in the adult hypoglossal nerve axotomy model

Recent studies have shown that hepatocyte growth factor (HGF) promotes the survival of embryonic motor neurons. However, it remains unclear whether HG F has trophic effects on mature motor neurons. In the present study, we exa mined the effects of HGF on adult motoneurons using the hypoglossal nerve t ransection model. In adult rats, neurons in the hypoglossal nucleus show a dramatic loss of choline acetyltransferase (ChAT) protein and mRNA after th e axotomy, This reduction of ChAT was markedly prevented when HGF was admin istered continuously at the cut end of the nerve using an osmotic pump. The HGF receptor, c-met, protein and mRNA, which were faintly expressed in hyp oglossal neurons under normal conditions, gradually increased and reached m aximal levels 2 weeks after the axotomy. Administration of HGF reduced this c-met upregulation almost to normal levels. We also quantified HGF mRNA in the tongue and hypoglossal nucleus. The tongue contained abundant HGF mRNA , whereas the nucleus contained only low levels. Interestingly, the HGF mRN A level in the nucleus did not increase after the axotomy. These findings s uggest that HGF is principally produced in the tongue and contributes to ma intain ChAT expression in the nucleus. HGF produced in the hypoglossal nucl eus alone after disconnection from the tongue may not be sufficient for the maintenance of the motor neuron function. Thus, exogenously applied HGF wa s effective to prevent the downregulation of ChAT activities. These finding s provide a strong rationale for the potential clinical use of HGF for the treatment of motor neuron degenerative disease.