Treatment with the flavonoid 7,8-Dihydroxyflavone: a promising strategy for a constellation of body and brain disorders

Emili, Marco; Guidi, Sandra; Uguagliati, Beatrice; Giacomini, Andrea; Bartesaghi, Renata; Stagni, Fiorenza

doi:10.1080/10408398.2020.1810625

Cited by 35 publications

(22 citation statements)

References 207 publications

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“…The DHF afforded neuroprotection was observed up to three weeks after IOP and, thus, lasted longer than our previously reported studies in which we administered a single intravitreal injection of BDNF after IONT [ 22 ] or crush [ 7 , 24 ]. DHF is known to activate TrkB receptor through its phosphorylation [ 40 , 43 , 46 ], and in our study the retinas treated with DHF showed a higher survival of RGCs and TrkB phosphorylation (pTrkB) at 7 days, thus suggesting that DHF reaches the retina and activates TrkB [ 45 ]. However, the signaling pathways responsible for the in vivo neuroprotective effects of DHF in the axotomized adult rat retina are, to the best of our knowledge, unknown.…”

Section: Introductionmentioning

confidence: 68%

“…The flavonoid 7,8-dihydroxyflavone (DHF) is a small molecule agonist of TrkB [ 35 ] and, thus, a mimetic of the neurotrophin BDNF [ 36 , 37 ] that has been studied recently as a neuroprotective drug in a number of experimental models of CNS diseases [ 36 , 38 , 39 ] (for review see [ 40 ]). In the retina, the effect of DHF has been studied in few experimental models: against excitotoxicity in isolated RGCs [ 41 ], or hypoxic-ischemic injury [ 42 ], both in vitro.…”

Section: Introductionmentioning

confidence: 99%

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7,8-Dihydroxiflavone Protects Adult Rat Axotomized Retinal Ganglion Cells through MAPK/ERK and PI3K/AKT Activation

Galindo‐Romero

Vidal‐Villegas

Asís‐Martínez

et al. 2021

IJMS

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We analyze the 7,8-dihydroxyflavone (DHF)/TrkB signaling activation of two main intracellular pathways, mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol 3 kinase (PI3K)/AKT, in the neuroprotection of axotomized retinal ganglion cells (RGCs). Methods: Adult albino Sprague-Dawley rats received left intraorbital optic nerve transection (IONT) and were divided in two groups. One group received daily intraperitoneal DHF (5 mg/kg) and another vehicle (1%DMSO in 0.9%NaCl) from one day before IONT until processing. Additional intact rats were employed as control (n = 4). At 1, 3 or 7 days (d) after IONT, phosphorylated (p)AKT, p-MAPK, and non-phosphorylated AKT and MAPK expression levels were analyzed in the retina by Western blotting (n = 4/group). Radial sections were also immunodetected for the above-mentioned proteins, and for Brn3a and vimentin to identify RGCs and Müller cells (MCs), respectively (n = 3/group). Results: IONT induced increased levels of p-MAPK and MAPK at 3d in DHF- or vehicle-treated retinas and at 7d in DHF-treated retinas. IONT induced a fast decrease in AKT in retinas treated with DHF or vehicle, with higher levels of phosphorylation in DHF-treated retinas at 7d. In intact retinas and vehicle-treated groups, no p-MAPK or MAPK expression in RGCs was observed. In DHF- treated retinas p-MAPK and MAPK were expressed in the ganglion cell layer and in the RGC nuclei 3 and 7d after IONT. AKT was observed in intact and axotomized RGCs, but the signal intensity of p-AKT was stronger in DHF-treated retinas. Finally, MCs expressed higher quantities of both MAPK and AKT at 3d in both DHF- and vehicle-treated retinas, and at 7d the phosphorylation of p-MAPK was higher in DHF-treated groups. Conclusions: Phosphorylation and increased levels of AKT and MAPK through MCs and RGCs in retinas after DHF-treatment may be responsible for the increased and long-lasting RGC protection afforded by DHF after IONT.

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Section: Introductionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

7,8-Dihydroxiflavone Protects Adult Rat Axotomized Retinal Ganglion Cells through MAPK/ERK and PI3K/AKT Activation

Galindo‐Romero

Vidal‐Villegas

Asís‐Martínez

et al. 2021

IJMS

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“…DHF has been shown to exert a number of protective functions, including anticancer [ 98 ] and anti-oxidative stress [ 99 ], but the finding that it is a high-affinity agonist of the tropomyosin-related kinase B (TrkB) receptor of brain-derived neurotrophic factor (BDNF) represented a milestone. Furthermore, added to its capacity to act as a BDNF mimetic, DHF was found to have several pharmacokinetic properties that make it advantageous for its use as neuroprotectant, and thus its potential has been explored experimentally in a number of BDNF-related neurodegenerative diseases (for review see Table 1 of [ 36 ]). However, until very recently, it was unknown if DHF could afford protection of adult rat RGCs in vivo [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, 7,8-Dihydroxiflavone, a potent TrkB agonist that acts as a BDNF mimetic (for review see [ 36 ]) and crosses the blood brain barrier [ 37 ], has been shown to prevent axotomy-induced RGC loss in adult rats in vivo [ 38 ] through TrkB signaling and subsequent activation of two main intracellular downstream pathways: mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol 3 kinase (PI3K)/AKT [ 39 ], that block both the intrinsic and extrinsic pathways of apoptosis [ 40 ]. However, at present we ignore whether the large proportion of RGCs rescued with DHF from axotomy-induced cell death maintain their functional properties.…”

Section: Introductionmentioning

confidence: 99%

7,8-Dihydroxiflavone Maintains Retinal Functionality and Protects Various Types of RGCs in Adult Rats with Optic Nerve Transection

Gallego‐Ortega

Vidal‐Villegas

Norte-Muñoz

et al. 2021

IJMS

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To analyze the neuroprotective effects of 7,8-Dihydroxyflavone (DHF) in vivo and ex vivo, adult albino Sprague-Dawley rats were given a left intraorbital optic nerve transection (IONT) and were divided in two groups: One was treated daily with intraperitoneal (ip) DHF (5 mg/kg) (n = 24) and the other (n = 18) received ip vehicle (1% DMSO in 0.9% NaCl) from one day before IONT until processing. At 5, 7, 10, 12, 14, and 21 days (d) after IONT, full field electroretinograms (ERG) were recorded from both experimental and one additional naïve-control group (n = 6). Treated rats were analyzed 7 (n = 14), 14 (n = 14) or 21 d (n = 14) after IONT, and the retinas immune stained against Brn3a, Osteopontin (OPN) and the T-box transcription factor T-brain 2 (Tbr2) to identify surviving retinal ganglion cells (RGCs) (Brn3a+), α-like (OPN+), α-OFF like (OPN+Brn3a+) or M4-like/α-ON sustained RGCs (OPN+Tbr+). Naïve and right treated retinas showed normal ERG recordings. Left vehicle-treated retinas showed decreased amplitudes of the scotopic threshold response (pSTR) (as early as 5 d), the rod b-wave, the mixed response and the cone response (as early as 10 d), which did not recover with time. In these retinas, by day 7 the total numbers of Brn3a+RGCs, OPN+RGCs and OPN+Tbr2+RGCs decreased to less than one half and OPN+Brn3a+RGCs decreased to approximately 0.5%, and Brn3a+RGCs showed a progressive loss with time, while OPN+RGCs and OPN+Tbr2+RGCs did not diminish after seven days. Compared to vehicle-treated, the left DHF-treated retinas showed significantly greater amplitudes of the pSTR, normal b-wave values and significantly greater numbers of OPN+RGCs and OPN+Tbr2+RGCs for up to 14 d and of Brn3a+RGCs for up to 21 days. DHF affords significant rescue of Brn3a+RGCs, OPN+RGCs and OPN+Tbr2+RGCs, but not OPN+Brn3a+RGCs, and preserves functional ERG responses after IONT.

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“…Therefore, the search for small molecular TrkB agonists that are able to cross the BBB and mimic BDNF’s action may lead to the development of a novel and effective therapy. 7,8-DHF has been postulated as a TrkB agonist and used as reference molecule for research into the TrkB receptor and development of new agonists [ 12 , 13 , 34 ]. However, the use of 7,8-DHF as a research tool to study TrkB agonism was questioned by other groups who were not able to confirm TrkB activation [ 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists

et al. 2021

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TrkB is a tyrosine kinase receptor that is activated upon binding to brain-derived neurotrophic factor (BDNF). To date, the search for low-molecular-weight molecules mimicking BDNF’s action has been unsuccessful. Several molecules exerting antidepressive effects in vivo, such as 7,8-DHF, have been suggested to be TrkB agonists. However, more recent publications question this hypothesis. In this study, we developed a set of experimental procedures including the evaluation of direct interactions, dimerization, downstream signaling, and cytoprotection in parallel with physicochemical and ADME methods to verify the pharmacology of 7,8-DHF and other potential reference compounds, and perform screening for novel TrkB agonists. 7,8 DHF bound to TrkB with Kd = 1.3 μM; however, we were not able to observe any other activity against the TrkB receptor in SN56 T48 and differentiated SH-SY5Y cell lines. Moreover, the pharmacokinetic and pharmacodynamic effects of 7,8-DHF at doses of 1 and 50 mg/kg were examined in mice after i.v and oral administration, respectively. The poor pharmacokinetic properties and lack of observed activation of TrkB-dependent signaling in the brain confirmed that 7,8-DHF is not a relevant tool for studying TrkB activation in vivo. The binding profile for 133 molecular targets revealed a significant lack of selectivity of 7,8-DHF, suggesting a distinct functional profile independent of interaction with TrkB. Additionally, a compound library was screened in search of novel low-molecular-weight orthosteric TrkB agonists; however, we were not able to identify reliable drug candidates. Our results suggest that published reference compounds including 7,8-DHF do not activate TrkB, consistent with canonical dogma, which indicates that the reported pharmacological activity of these compounds should be interpreted carefully in a broad functional context.

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Treatment with the flavonoid 7,8-Dihydroxyflavone: a promising strategy for a constellation of body and brain disorders

Cited by 35 publications

References 207 publications

7,8-Dihydroxiflavone Protects Adult Rat Axotomized Retinal Ganglion Cells through MAPK/ERK and PI3K/AKT Activation

7,8-Dihydroxiflavone Protects Adult Rat Axotomized Retinal Ganglion Cells through MAPK/ERK and PI3K/AKT Activation

7,8-Dihydroxiflavone Maintains Retinal Functionality and Protects Various Types of RGCs in Adult Rats with Optic Nerve Transection

Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists

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