6-7-dihydroxyflavone and Neurodegenerative-Diseases

7,8-dihydroxyflavone (DHF), a naturally-occurring plant-based flavone, is a high-affinity tyrosine kinase receptor B (TrkB) agonist and a bioactive molecule of therapeutic interest for neuronal survival, differentiation, synaptic plasticity and neurogenesis. In the family of neurotrophic factors, this small BDNF-mimetic molecule has attracted considerable attention due to its oral bioavailability and ability to cross the blood-brain barrier. Recent evidences have shed light on the neuroprotective role of this pleiotropic flavone against several neurological disorders, including Alzheimer's disease, Parkinson's disease, cerebral ischemia, Huntington's disease, and other CNS disorders. DHF also elicits potent protective actions against toxins-induced insults to brain and neuronal cells. DHF shows promising anti-oxidant and anti-inflammatory properties in ameliorating the neurodegenerative processes affecting the CNS. This review provides an overview of the significant neuroprotective potentials of DHF and discusses how it exerts its multitudinous beneficial effects by modulating different pathways linked with the pathophysiology of CNS disorders, and thus proposes it to be a nutraceutical against a broad spectrum of neurological disorders.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Central Nervous System Diseases; Dietary Supplements; Flavones; Humans; Neurodegenerative Diseases; Neuroprotective Agents

Parkinson's disease (PD) is the most common motor-associated neurodegenerative disease. Although the pathogenesis of PD is still wrapped in the mist, accumulating evidence indicates that mitochondrial dysfunction contributes to the onset and progression of PD. We previously reported that the lysosomal protease asparagine endopeptidase (AEP) cleaves α-synuclein in the brains of PD patients. The major product, α-synuclein 1-103, significantly promotes PD-like histological changes and motor dysfunction. However, the underlying molecular mechanisms remain unknown. Here we show that α-synuclein 1-103 fragment interacts with mitochondria and induces morphological and functional abnormalities of mitochondria. Furthermore, we investigated the protective effects of 7,8-dihydroxyflavone (7,8-DHF) on mitochondrial dysfunction induced by α-synuclein 1-103 fragment. We found that 7,8-DHF ameliorated α-synuclein 1-103-induced mitochondrial impairment and motor dysfunction. These results indicate that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating PD.

Topics: alpha-Synuclein; Animals; Flavones; Humans; Mice; Mice, Transgenic; Mitochondria; Neurodegenerative Diseases; Parkinson Disease

7,8-Dihydroxyflavone (7,8-DHF) is a natural flavonoid compound that act as Trk-B agonist. 7,8-DHF is also a potent antioxidant. When applied systematically, 7,8-DHF can pass through blood-brain barrier and exhibit potential therapeutic effects in several animal models of neurodegenerative disorders. This study investigates the remedial effects of 7,8-DHF on behavioral impairments and biochemical changes associated with aging with a species emphasis on cortex. For this purpose three experimental groups were formed which are young control group, old group and old-DHF groups. 5 mg/kg 7,8-DHF was administered intraperitoneally to old-DHF group for 3 weeks. We assessed the hang wire and adhesive removal performances of mice. Also, oxidative stress, neuroinflammation and synaptic protein levels in the cortex were measured. We observed that chronic administration of 7,8-DHF improved behavioral performance of old mice. Besides, 7,8-DHF reversed MDA level which was increased in old control animals. However, 3 weeks application of 7,8-DHF failed to recover the levels of neuroinflammation markers (TNF-α and IL-6) and synaptic proteins (PSD-95 and Synaptophysin) which were reduced in old group. These findings demonstrate that improvement of age-dependent behavioral impairments and MDA levels by 7,8-DHF could be attributed to its antioxidant actions.

Topics: Aging; Animals; Antioxidants; Behavior, Animal; Flavones; Lipid Peroxidation; Malondialdehyde; Mice; Neurodegenerative Diseases

Oxidative stress-induced neuronal death plays a pivotal role in pathogenesis of neurodegenerative disorders. Recently, 7,8-dihydroxyflavone (7,8-DHF) has been shown to exert neuroprotective effects by acting as a selective tyrosine kinase receptor B (TrkB) agonist. In addition, the antioxidant action of 7,8-DHF may protect neuronal cells against oxidative injury. In the present study, we used PC12 cells, a cell line generally thought to lack TrkB, to investigate the effect of 7,8-DHF on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity and the underlying mechanism. We found that 7,8-DHF effectively prevented cell death, apoptosis and mitochondrial dysfunction induced by 6-OHDA. In a cell free system, 7,8-DHF did not slow down extracellular auto-oxidation of 6-OHDA which may generate H2O2. However, We found that 7,8-DHF dramatically reduced cellular malondialdehyde content and phospho-histone H2A.X protein level. 7,8-DHF also elevated total superoxide dismutase activity in 6-OHDA-treated cells. These results indicate that 7,8-DHF might protect PC12 cells against 6-OHDA-induced cytotoxicity through its powerful antioxidant activity. By acting as a potent TrkB agonist and an antioxidant together with its easiness to pass across blood-brain barrier, 7,8-DHF may be developed into a promising candidate in treatment of neurodegenerative diseases.

Topics: Animals; Antioxidants; Cell Death; Cell Line; Flavones; Hydrogen Peroxide; Hydroxydopamines; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Rats; Reactive Oxygen Species

Topics: Amygdala; Animals; Brain-Derived Neurotrophic Factor; Conditioning, Classical; Disease Models, Animal; Extinction, Psychological; Flavones; Genetic Therapy; Humans; Learning; Memory; Mental Disorders; Mice; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Receptor, trkB; Signal Transduction