Pros and cons of 7,8-DHF and it's 4'-DMA analogue for neuropathologies Disrupted white matter integrity may lead to impaired functional connectivity of the neuronal networks, resulting in cognitive and motor deficits as well as long-lasting behavioral disturbances. Pharmacological interventions which can preserve brain structure and promote plasticity may show promise for improving neurological outcome 7,8-DHF, a compound extensively studied in the context of neurodegenerative diseases, can exert a protective effect on the injured white matter of the aging rodent brain through mitigation of axonal damage and loss of mature oligodendrocytes. - may influence plasticity mechanisms that are associated with functional recovery - improved neurobehavioral outcome was observed in experimental studies involving various cognitively impaired animal models Pros of 7,8-DHF - acts as potent antidepressant drug in mice through activating TrkB receptor. - Present in plant species, including Godmania aesculifolia, Tridax procumbens, and several species of Primula, these plants have been used since ancient times in herbal and traditional medicine for the treatment of various ailments. Leaf, stem, or whole plant extract of T. 1 procumbens has been shown to have potent immunomodulatory, antioxidant, and anti- inflammatory activities. Products like powdered leaves, oils, tea, leaf juice, etc. are being produced using parts of these species - The toxicity profile of DHF has been explored in cellular as well as animal model systems. In the hippocampal cellular model, DHF is well-tolerated in different concentrations ranging from 1 μM to 80 μM. However, cell viability decreases at 100 μM (Chen et al., 2011). No detectable toxicity is observed in mouse and monkey models even after chronic treatment (Liu et al., 2010; Blugeot et al., 2011). Similarly, in monkey model, long-term (7 months) oral dose of DHF (30 mg/kg/day) did not cause any deterioration of health state - both compounds, 7,8-DHF and 4'-DMA-7,8-DHF reveal comparable antidepressant effects at 5 mg/kg. Cons of 7,8-DHF : - poor water solubility, chemical instability, subsequent suboptimal oral bioavailability and minimal brain exposure have become its primary limiting factors restricting its therapeutic potential - oral bioavailability of about 5%, a half-life of 134 min in plasma of mouse and 4–8 h in plasma of monkey Pros of 4'-DMA-7,8-DHF - exhibits a higher agonistic activity and more prolonged effect in mouse brain than 7,8-DHF - at a dose of 1 mg/kg, 4,-DMA-7,8-DHF displays a more potent antidepressant effect than 7,8-DHF No appreciable adverse pathological change was detectable in the drug-treated mice, a complete blood count (CBC) analysis shows that there is no significant difference between drug-treated and the control saline-treated mice. Hence, these data support that both compounds are not toxic to the mice at 5 mg/kg dose over the 3-week chronic treatment Can piperine enhance 7,8-DHF bioavailability? Polyphenol bioavailability has been enhanced using piperine, where piperine increases the Cmax and degree of exposure (i.e. AUC) to various polyphenols, which appears to be through the inhibition of glucuronidation and sulfotransferases (UGTs and SULTs) References: Rajib Paul, Joyobrato Nath, Satinath Paul, Muhammed Khairujjaman Mazumder, Banashree Chetia Phukan, Rubina Roy, Pallab Bhattacharya, Anupom Borah Suggesting 7,8- dihydroxyflavone as a promising nutraceutical against CNS disorders, Neurochemistry 2 International, Volume 148, 2021, 105068, doi:10.1016/j.neuint.2021.105068 Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K, Phun LH, France S, Xiao G, Jia Y, Luo HR, Ye K. A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect. J Med Chem. 2010 Dec 9;53(23):8274-86. doi: 10.1021/jm101206p. Zeng, Xiaohui & Cai, Dake & Zeng, Qiaohuang & Chen, Zhao & Zhong, Guoping & Zhuo, Juncheng & Gan, Haining & Huang, Xuejun & Zhao, Ziming & Yao, Nan & Huang, Dane & Zhang, Chengzhe & Sun, Dongmei & Chen, Yuxing. (2016). Selective Reduction in the Expression of UGTs and SULTs, a Novel Mechanism by which Piperine Enhances the Bioavailability of Curcumin in Rat: Novel mechanism of piperine improving bioavailability of Curcumin. Biopharmaceutics & Drug Disposition. doi:38. 10.1002/bdd.2049 3