7,8-Dihydroxyflavone facilitates the action exercise to restore plasticity and functionality: Implications for early brain trauma recovery

Abstract

Metabolic dysfunction accompanying traumatic brain injury (TBI) severely impairs the ability of injured neurons to comply with functional demands. This limits the success of rehabilitative strategies by compromising brain plasticity and function, and highlights the need for early interventions to promote energy homeostasis. We sought to examine whether the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) normalizes brain energy deficits and restablishes more normal patterns of functional connectivity, while enhancing the effects of exercise during post-TBI period. Moderate fluid percussion injury (FPI) was performed and 7,8-DHF (5 mg/kg, i.p.) was administered in animals subjected to FPI that either had access to voluntary wheel running for 7 days after injury or were sedentary. Compared to sham-injured controls, TBI resulted in reduced hippocampal activation of the BDNF receptor TrkB and associated CREB, reduced levels of plasticity markers GAP-43 and Syn I, as well as impaired memory as indicated by the Barnes maze task. While 7,8-DHF treatment and exercise individually mitigated TBI-induced effects, administration of 7,8-DHF concurrently with exercise facilitated memory performance and augmented levels of markers of cell energy metabolism viz., PGC-1α, COII and AMPK. In parallel to these findings, resting-state functional MRI (fMRI) acquired at 2 weeks after injury showed that 7,8-DHF with exercise enhanced hippocampal functional connectivity, and suggests 7,8-DHF and exercise to promote increases in functional connectivity. Together, these findings indicate that post-injury 7,8-DHF treatment promotes enhanced levels of cell metabolism, synaptic plasticity in combination with exercise increases in brain circuit function that facilitates greater physical rehabilitation after TBI.

Blueberry Supplementation Mitigates Altered Brain Plasticity and Behavior after Traumatic Brain Injury in Rats

“…In agreement with previous reports, we found that TBI impairs spatial learning as evidenced by an increase in latency in the Barnes maze, while BB supplementation decreased latency time to find the escape hole at each training day. We assessed the use of spatial learning strategies in our paradigm to provide a complementary measure of cognitive function less dependent on motor behavior.…”

“…We employed our standard lateral FPI protocol as described earlier . Briefly, 3% isoflurane (1.0 mL min −1 in 100% oxygen) was provided in a chamber (VetEquip Inc., CA, USA), and then maintained with 2–2.5% isoflurane via nose cone while rats were in a stereotaxic frame.…”

“…Specifically, rats were individually placed in the closed arm of the EPM apparatus and permitted free exploration for 5 min during which their movements were camera recorded . The behaviors scored were time spent and number of entries into the open arm using automated video tracking system (AnyMaze, San Diego Instruments, CA, USA) . EPM testing was conducted after Barnes maze memory test.…”

7,8-dihydroxyflavone Improves Neuropathological Changes in the Brain of Tg26 Mice, A Model for HIV-associated Neurocognitive Disorder

“…Just as we found in the Tg26 model, PGC-1a levels are reduced in HIV + brains exposed to ART [32]. In a TBI model, it was previously established that DHF restored levels of PGC-1a [101]. This mechanism, similar to that of what we present in our animal model of HAND ( Fig.…”

“…This mechanism, similar to that of what we present in our animal model of HAND ( Fig. 6A-H), is likely TrkB dependent, as the BDNF receptor activates the cAMP-response-element-binding protein (CREB), a transcription factor that regulates PGC-1a [101]. Low PGC-1α levels is associated with stimulating NF-kB activation, as seen in our Tg26 model, suggesting a link between metabolic disturbances and the in ammatory response.…”