Amyotrophic lateral sclerosis (ALS) is an enigmatic neurodegenerative disorder without any effective treatment characterized by loss of motor neurons (MNs) that results in rapidly progressive motor weakness and early death due to respiratory failure. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family known to play a prominent role in the differentiation and survival of MNs. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) is a potent and selective small molecule tyrosine kinase receptor B (TrkB) agonist that mimics the effects of BDNF. In the present study, we evaluated the neuroprotective effects of 7,8-DHF in a transgenic ALS mouse model (SOD1G93A). We found that chronic administration of 7,8-DHF significantly improved motor deficits, and preserved spinal MNs count and dendritic spines in SOD1G93A mice. These data suggest that 7,8-DHF should be considered as a potential therapy for ALS and the other motor neuron diseases.

The ventral anterior nucleus of the thalamus (VATh) gathers motor information from the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNpr) of the basal ganglia and projects directly to motor areas of cortex. GPi/SNpr send their tonically active gamma-aminobutyric acid (GABA)ergic outputs to VATh. The abnormal firing patterns of GABAergic neurons in GPi/SNpr lead to motor deficits. In Parkinson's disease, the spontaneous firing pattern of GPi/SNpr neurons is abnormal due to the degeneration of the nigrostriatal dopaminergic pathway. In a previous study, we found that systemically administered vasoactive intestinal peptide (VIP) was effective at reversing the motor deficits (but not the decline in striatal dopamine levels) in a rat model of Parkinson's disease (6-hydroxydopamine (6-OHDA) exposure). In addition to the beneficial effects on the motor response, VIP could also attenuate both neuronal cell death and the characteristic loss of the myelin sheath that is associated with 6-OHDA administration into the rat striatum. VIP was thought to preserve neurons by inducing native brain mast cells to adopt a nondegranulating phenotype that had the ability to secrete numerous neuroprotective substances, such as nerve growth factor (NGF) and heparin. In the present study, the effect of systemically administered VIP (25 ng/kg i.p.) was investigated on GABA levels of the VATh, dopamine/3,4-dihydroxyphenylacetic acid (DOPAC) levels in the corpus striatum, and the NGF, rat mast cell protease II (RMCPII), serotonin, and heparin content of brain mast cells in 6-OHDA-lesioned rats. Extracellular concentrations of GABA, dopamine, and DOPAC were measured by microdialysis and high-performance liquid chromatography. NGF, RMCPII, serotonin, and heparin levels were examined by immunohistochemical staining techniques. A total of 48 young adult Sprague-Dawley rats were used in the study, and these were assigned to one of six groups. Unilateral injection of 6-OHDA, 2 microl (6 mg/microl), was made into the right corpus striatum. VIP-treated animals received 25 ng/kg VIP i.p. at 2-day intervals for a period of 15 days. The present results demonstrated that VIP significantly increased the levels of GABA in the VATh that were reduced by 6-OHDA application and increased the number of NGF-immunoreactive mast cells but did not alter dopamine metabolism. Therefore, the protective effect of VIP on motor function is possibly related to the increased levels of GABA in the VATh, and its neuroprotective actions may be mediated by the release of NGF from brain mast cells.

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