7,8-Dihydroxyflavone facilitates the action exercise to restore plasticity and functionality: Implications for early brain trauma recovery.
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 reestablishes 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 (5mg/kg, i.p.) was administered in animals subjected to FPI that either had access to voluntary wheel running for 7days 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 2weeks 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.
Department of Integrative Biology & Physiology, University of California, Los Angeles, CA, USA.
Gokul
G
Krishna
Department of Integrative Biology & Physiology, University of California, Los Angeles, CA, USA.
Rahul
R
Agrawal
Department of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, CA, USA.
Yumei
Y
Zhuang
Department of Integrative Biology & Physiology, University of California, Los Angeles, CA, USA.
Zhe
Z
Ying
Department of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, CA, USA.
Afshin
A
Paydar
Department of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, CA, USA.
Neil G
NG
Harris
Exercise and Biochemistry Laboratory, Center of Physical Education and Sports (CEFD), Federal University of Santa Maria, Santa Maria, Brazil.
Luiz Fernando F
LFF
Royes
Department of Integrative Biology & Physiology, University of California, Los Angeles, CA, USA; Department of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, CA, USA. Electronic address: fgomezpi@ucla.edu.
Fernando
F
Gomez-Pinilla
D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000534:rehabilitation*; D047309:Flavones / Q000494:pharmacology*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects*; D010805:Physical Conditioning, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley
D047309:Flavones
7,8-Dihydroxyflavone; Exercise; Functional connectivity; Memory; Rehabilitation; Traumatic brain injury