Salidroside directly activates HSC70, revealing a new role for HSC70 in BDNF signalling and neurogenesis after cerebral ischemia

 What is your doctor's EXACT PROTOCOL for getting you BDNF?

If your doctor doesn't know of all these BDNF stroke research articles there is a good reason!  PURE INCOMPETENCE!

• BDNF (170 posts to April 2011)

 

Salidroside directly activates HSC70, revealing a new role for HSC70 in BDNF signalling and neurogenesis after cerebral ischemia

Wenfang Lai, Rui Luo, Yuheng Tang, Zhengshuang Yu, Binbin Zhou, Zelin Yang, John Brown, Guizhu Hong

First published: 15 March 2024

https://doi.org/10.1002/ptr.8178

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Abstract

Salidroside, a principal bioactive component of Rhodiola crenulata, is neuroprotective across a wide time window in stroke models. We investigated whether salidroside induced neurogenesis after cerebral ischemia and aimed to identify its primary molecular targets. Rats, subjected to transient 2 h of middle cerebral artery occlusion (MCAO), received intraperitoneal vehicle or salidroside ± intracerebroventricular HSC70 inhibitor VER155008 or TrkB inhibitor ANA-12 for up to 7 days. MRI, behavioural tests, immunofluorescent staining and western blotting measured effects of salidroside. Reverse virtual docking and enzymatic assays assessed interaction of salidroside with purified recombinant HSC70. Salidroside dose-dependently decreased cerebral infarct volumes and neurological deficits, with maximal effects by 50 mg/kg/day. This dose also improved performance in beam balance and Morris water maze tests. Salidroside significantly increased BrdU⁺/nestin⁺, BrdU⁺/DCX⁺, BrdU⁺/NeuN⁺, BrdU⁻/NeuN⁺ and BDNF⁺ cells in the peri-infarct cortex, with less effect in striatum and no significant effect in the subventricular zone. Salidroside was predicted to bind with HSC70. Salidroside dose-dependently increased HSC70 ATPase and HSC70-dependent luciferase activities, but it did not activate HSP70. HSC70 immunoreactivity concentrated in the peri-infarct cortex and was unchanged by salidroside. However, VER155008 prevented salidroside-dependent increases of neurogenesis, BrdU⁻/NeuN⁺ cells and BDNF⁺ cells in peri-infarct cortex. Salidroside also increased BDNF protein and p-TrkB/TrkB ratio in ischemic brain, changes prevented by VER155008 and ANA-12, respectively. Additionally, ANA-12 blocked salidroside-dependent neurogenesis and increased BrdU⁻/NeuN⁺ cells in the peri-infarct cortex. Salidroside directly activates HSC70, thereby stimulating neurogenesis and neuroprotection(Never use the word neuroprotection, it doesn't signify urgency; whereas the neuronal cascade of death suggests extreme urgency)

via BDNF/TrkB signalling after MCAO. Salidroside and similar activators of HSC70 might provide clinical therapies for ischemic stroke.

 

 

 

 

 

Psychedelic-induced BDNF/TrkB signaling as a mechanism for increased neuroplasticity

This says something, but I can't figure it out.

Psychedelic-induced BDNF/TrkB signaling as a mechanism for increased neuroplasticity

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http://urn.fi/URN:NBN:fi:hulib-202212144071

	Psychedelic-induced BDNF/TrkB signaling as a mechanism for increased neuroplasticity
	Haapaniemi, Hele
	Helsingin yliopisto, Lääketieteellinen tiedekunta University of Helsinki, Faculty of Medicine Helsingfors universitet, Medicinska fakulteten
	Helsingin yliopisto
	2022
	eng
	http://urn.fi/URN:NBN:fi:hulib-202212144071 http://hdl.handle.net/10138/351753
	master's thesis
	The prevalence of major depressive disorder is increasing despite the increased standard of living. The prevailing hypothesis to explain depression is that there is an unbalance in information processing in relevant brain networks. Antidepressants (SSRIs, SNRIs) have been shown to induce a juvenile-like plasticity state (iPlasticity) in the brain that helps in rewiring the affected neuronal networks when combined with beneficial environmental stimuli (e.g. psychotherapy). However, it takes weeks to see the beneficial effects of conventional antidepressants on mood and they bring relief only to approximately two-thirds of the patients. There is an urgent need for more efficient and rapid-acting antidepressants. Preliminary data suggests that psychedelics may have potential to respond to this need. It is thought that the therapeutic effect of psychedelics rises from the molecular effects leading to structural and functional plasticity and behavioral changes. Molecular effects of psychedelics are believed to arise from the activation of serotonin 2A (5-HT2A) receptors. It is well established that serotonin 2A (5-HT2A) receptor activation lies behind the hallucinogenic effects of psychedelics, but its role in drug-induced plasticity is currently under debate. Signaling of brain-derived neurotrophic factor (BDNF) through its receptor TrkB has been proposed to underlie the plasticity-promoting effects of psychedelics. However, the mechanisms leading to increased BDNF/TrkB signaling after psychedelic administration are poorly understood. This thesis aimed to study the molecular mechanisms associated with psychedelic-induced plasticity in cortical neuronal cultures. The timeline of the effects of LSD was studied by analyzing the phosphorylation of neurotrophic signaling markers downstream of TrkB (mTOR and ERK) in primary neuronal cultures using Western blot. The role of the 5-HT2A receptor was assessed by combining 5-HT2A antagonist M100907 pretreatment with LSD treatment, followed by Western blot analyses of the same signaling markers mTOR and ERK. The degree of molecular effects of psychedelics was compared to the effects of classical antidepressant fluoxetine. Protein-fragment complementation assay (PCA) was used to evaluate the dimerization of the TrkB receptor in the presence of psychedelics and classical antidepressants. In this context, Western blot was also used to assess the phosphorylation of the plasticity-related BDNF signaling markers ERK and two tyrosines of TrkB receptor (Y515 and Y816) that mediate recruitment of neurotrophic signaling pathways. We found that psychedelic treatment promoted phosphorylation of mTOR and ERK significantly. These effects were not affected by pretreatment with M100907, indicating activation of BDNF/TrkB signaling by psychedelics is independent from 5-HT2A activation. Psychedelics were also shown to cause a significant increase in dimerization of TrkB whereas increase caused by fluoxetine was not significant. Lastly, psychedelics were shown to cause increase in phosphorylation of TrkB and ERK that were comparable to those induced by fluoxetine. These results highlight the potential of psychedelics to promote BDNF-mediated neurotrophic signaling associated with juvenile-like plasticity. Interestingly, the results show recruitment of BDNF/TrkB downstream signaling independently from 5-HT2A activation, which suggests that plasticity-promoting effects of psychedelics might be detached from their hallucinogenic effects.