7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis

Abstract

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.

Neurotrophin signalling: novel insights into mechanisms and pathophysiology

“…BDNF has been reported to slow progression of motor neuron atrophy in an animal model of ALS [90]. Moreover, the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) improved motor neuron deficits in the superoxide dismutase 1 (SOD1) (G93A) ALS mouse model [91], although efforts to replicate the positive effects of 7,8-DHF upon TrkB activity have not been successful [92]. An alternative approach is to use agonist monoclonal antibodies for TrkB [92].…”

Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies

“…7,8-DHF acts as a selective and efficient TrkB agonist and presents neuroprotective effects in excitotoxic processes induced in vitro [199] or using in vivo models of brain ischemia [198], AD [200], ALS [201] or PD [198], among others. Thus, flavonoid-based TrkB agonists are currently considered as very promising compounds to treat stroke and neurodegenerative diseases.…”

Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease

“…BDNF has been reported to slow progression of motor neuron atrophy in the wobbler mice, an animal model of ALS (Mitsumoto et al, 1994). Additionally, the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) ameliorated motor neuron deficits in the SOD1 (G93A) ALS mouse model (Korkmaz et al, 2014), although efforts to replicate the positive effects of 7,8-DHF upon TrkB activity have been unsuccessful (Todd et al, 2014). Despite the therapeutic potential of BDNF, previous clinical trials in ALS patients have failed due to difficulties in administered BDNF to reach degenerating neurons (Anon., 1999).…”