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Flavonoids with Preclinical Antidepressant-Like Effects
Published in Scott Mendelson, Herbal Treatment of Major Depression, 2019
7,8,dihydroxyflavone is a flavonoid found in a number of herbs, including Godmania aesculifolia, Tridax procumbens, and primula tree leaves. It has been the subject of intense research after reports that it acts as a centrally active, small molecule, selective TrkB agonist.21 Activation of the TrkB receptors appears necessary for antidepressant action.22 Thus, the significance of such a molecule in the treatment of MDD is readily apparent. So many authors have reported that 7,8,dihydroxyflavone activates the TrkB receptor that it appeared to have become an established fact. However, at least one group found discrepancies in this conclusion.23 In any case, whether due to activation of TrkB receptor or not, 7,8,dihydroxyflavone has been reported to have antidepressant-like effects in rodents.
Diet and exercise interventions to promote metabolic homeostasis in TBI pathology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
The extraordinary capacity of BDNF to support several aspects of brain plasticity and function is negated by the poor pharmacokinetic profile of BDNF. Agents that stimulate the TrkB receptor could be ideal therapeutic agents to combat the TBI pathology without the poor pharmacokinetics of BDNF. This is a desired goal because BDNF and TrkB signaling are reduced in the TBI pathology,93 thereby reducing neuronal function and making neurons more vulnerable to secondary challenges. The 7,8-dihydroxyflavone (7,8-DHF) is a member of the flavonoid family of compounds present in fruits and vegetables, which can mimic BDNF signaling through the TrkB receptor.94 Furthermore, the facts that 7,8-DHF crosses the blood–brain barrier and has a safe pharmacokinetic profile make 7,8-DHF an excellent therapeutic agent.94,95 The binding of 7,8-DHF to the cysteine cluster 2 and leucine-rich region in the extracellular domain of the TrkB receptor provokes TrkB receptor dimerization and autophosphorylation, which leads to activation of downstream signaling cascades similar to BDNF. In particular, 7,8-DHF has demonstrated neuroprotective effects against oxidative stress incurred from glutamate toxicity,96 decreases infarct volumes in stroke, and reduces toxicity in an animal model of Parkinson’s disease.94 These features portray 7,8-DHF as an ideal candidate to be used therapeutically to counteract the effects of the TBI pathology. Systemic administration of 7,8-DHF using an animal model of TBI has been shown to significantly attenuate disrupted memory function by activating hippocampal TrkB receptor.97 In addition, the 7,8-DHF treatment was effective in ameliorating the effects of TBI on CREB phosphorylation, GAP-43, and syntaxin-3 levels. The action of 7,8-DHF engaged molecular systems important for energy homeostasis (AMPK and SIRT1) and mitochondrial biogenesis (PGC-1α, TFAM, and COII), indicating that activation of cellular energy metabolism may be an important step for the action of 7,8-DHF on plasticity. Information gathered so far portrays the potential of 7,8-DHF as an efficacious and noninvasive therapeutic agent to downgrade the TBI pathology.
Is neurotrophin-3 (NT-3): a potential therapeutic target for depression and anxiety?
Published in Expert Opinion on Therapeutic Targets, 2020
A. S. de Miranda, J. L. V. M. de Barros, Antonio Lucio Teixeira
More recently, studies have focused on the design and/or identification of neurotrophin-mimetic compounds that can cross the blood–brain barrier when administered peripherally and influence the CNS functions. These studies prioritized BDNF agonists, showing that flavone derivative compounds (7,8-dihydroxyflavone and 4ʹ-dimethylamino-7,8-dihydroxyflavone) and the low-molecular-weight mimetic GSB-106, a substituted dimeric dipeptide bis (N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, activate BDNF/TrkB downstream signaling pathways and exert antidepressant effects [132–135]. Regarding the NT3/TrkC signaling pathway, peptidomimetic ligands of TrkC were also synthesized and seem to exert NT-3 mediated biological effects like to promote cell survival, neurite outgrowth, and axonal branching [136,137]. Although these peptides appear to successfully mimic the NT3/TrkC biological actions, evidence that they exert protective effects in neuropsychiatry disorders like depression and anxiety is still required. Preclinical studies with rodents and monkeys have shown that NT-3-loaded chitosan biodegradable material, immediately implanted into the injured area, exerts neuroprotective effects in neurological conditions, like TBI and spinal cord injury [40–43].
Orexin/hypocretin receptor, Orx1, gene variants are associated with major depressive disorder
Published in International Journal of Psychiatry in Clinical Practice, 2019
Mujgan Cengiz, Vilson Karaj, Nese Kocabasoğlu, Gokcen Gozubatik-Celik, Ahmet Dirican, Burcu Bayoglu
Feng et al. quantified orexin A levels from mouse hypothalamic tissue. In their study, mice treated with 7,8-Dihydroxyflavone (DHF) which was recently identified as a Tropomyosin-receptor-kinase B (Trk B) agonist ameliorating depression, exhibited significantly lower orexin A levels compared with mice treated with vehicle. However no significant relation was reported in orexin B levels between the two groups (Feng et al., 2015). In another study, orexin A levels were measured in cerebrospinal fluid (CSF) of MDD, dysthymia and adjustment disorder patients after a suicide attempt and orexin A levels were diminished in MDD patients than in dysthymia and adjustment disorder. Also, orexin neurons were reported to be reduced in hypothalamus in post-mortem tissue (Brundin, Björkqvist, Petersén, & Träskman-Bendz, 2007). On the other hand, Schmidt et al. investigated orexin levels in CSF of MDD patients without psychiatric comorbidities. They reported mean orexin A levels did not differ significantly between MDD subjects and controls (Schmidt et al., 2011).
Huntington’s disease: novel therapeutic perspectives hanging in the balance
Published in Expert Opinion on Therapeutic Targets, 2018
Ana Saavedra, Gerardo García-Díaz Barriga, Esther Pérez-Navarro, Jordi Alberch
Since BDNF protein-based therapies have several limitations, an alternative would be to use small agonists of its high-affinity receptor. Actually, the TrkB agonist LM22A-4 reduced motor impairment, inflammation and mHtt aggregates and prevented spine loss in R6/2 and BACHD mouse models of HD [104]. Treatment with 7,8-dihydroxyflavone (7,8-DHF), originally described as a potent and selective TrkB agonist [105], also promoted motor and pathological improvements and extended survival in N171-82Q mice [106]. Another recent study demonstrates that chronic administration of 7,8-DHF delayed motor deficits and prevented deficits in object recognition memory in R6/1 mice. This behavioral amelioration correlated with improved striatal levels of enkephalin, prevention of striatal volume loss and reduced mHtt aggregates, together with normalized striatal levels of induced and neuronal nitric oxide synthase (NOS) [107].