Amyotrophic lateral sclerosis (ALS) is an enigmatic neurodegenerative disorder characterized by the selective loss of motor neurons that results in rapid progressive motor weakness and early death due to respiratory failure. The etiology of neurodegeneration in ALS is not known but likely arises from a combination of mechanisms, including protein misfolding, mitochondria dysfunction, oxidative damage, defective axonal transport, excitoxicity, deficient growth factor signaling, and inflammation. A very recent report shows that SOD1 mutant-mediated endothelial damage develops before motor neuron degeneration followed later by a neurovascular inflammatory response suggesting that endothelial damage is a key contributor to disease initiation. 7,8-dihydroxyflavone (7,8-DHF) is a member of the flavonoid family. Flavonoids, present in fruits and vegetables, have been shown to exert diverse biological actions including neuroprotective, anti-oxidant and anti-apoptotic properties. It has been shown that flavonoids improved spatial memory and this effect was associated with increased angiogenesis and neuronal spine density in the dentate gyrus of the hippocampus in mice. Furthermore, improvement in spatial memory was enhanced in combination with exercise. Flavonoids exert effects on long-term potentiation underlying learning and memory, on and consequently memory and cognitive performance, through their interactions with the signaling pathways including PI3K/Akt. Most recently, 7,8-DHF was shown to bind with high affinity to the TrkB receptor and provoke its dimerization and autophosphorylation, leading to downstream-signaling cascade activation. Systemic administration of this compound in mice substantially activates TrkB in the brain, inhibits neuronal cell death, decreases infarct volumes in stroke in a TrkB-dependent manner, and is neuroprotective in an animal model of Parkinson's disease and stroke. This data indicate that 7,8-dihydroxyflavone shows it's effects as a potent and selective TrkB agonists that virtually mimic BDNF's biochemical and physiological actions by activating similar signaling mechanism. The effects of 7,8-dihydroxyflavone suggest that it could be a powerful therapeutic drug for the treatment of neurological diseases. We will monitor the effects of 7,8-DHF administration on body weight, motor performance and longevity and examine the effects on motor neuron and ventral horn changes in size, number, dendritic branching, spine density using histopathological, neurochemical techniques and magnetic resonance imaging (MRI) post mortem and in vivo. In addition neurochemical markers for neuronal health (N- acetylaspartate) and glial markers (myo-inosotol, taurine) will be detected using magnetic resonance spectroscopy in ALS mice. We will further evaluate blood spinal cord barrier changes using in vivo MRI of the spinal cord in the ALS mice. We will use neurochemical techniques to measure BDNF, and neuropathological/stereological techniques to quantify biomarkers in the spinal cord. The novel studies we propose will produce data to improve our understanding of disease mechanisms and test the beneficial effects of 7,8-DHF in ALS.
Military personnel have a greater risk of developing amyotrophic lateral sclerosis (ALS). Consistent with special request for applications to focus on improving our understanding of the etiology, pathogenesis, and/or genetics of amyotrophic lateral sclerosis, this study proposes to integrate neuroimaging with neurochemical/neuropathological methods to apply on a transgenic mouse model of ALS in order to produce data that are applicable to human disease conditions. Veterans at risk and those affected by ALS will directly benefit from the outcome of the proposed studies.