Facilitating Mitochondrial Calcium Uptake Improves Activation-Induced Cerebral Blood Flow and Behavior after mTBI

Abstract

Mild to moderate traumatic brain injury (mTBI) leads to secondary neuronal loss via excitotoxic mechanisms, including mitochondrial Ca2+ overload. However, in the surviving cellular population, mitochondrial Ca2+ influx, and oxidative metabolism are diminished leading to suboptimal neuronal circuit activity and poor prognosis. Hence we tested the impact of boosting neuronal electrical activity and oxidative metabolism by facilitating mitochondrial Ca2+ uptake in a rat model of mTBI. In developing rats (P25-P26) sustaining an mTBI, we demonstrate post-traumatic changes in cerebral blood flow (CBF) in the sensorimotor cortex in response to whisker stimulation compared to sham using functional Laser Doppler Imaging (fLDI) at adulthood (P67-P73). Compared to sham, whisker stimulation-evoked positive CBF responses decreased while negative CBF responses increased in the mTBI animals. The spatiotemporal CBF changes representing underlying neuronal activity suggested profound changes to neurovascular activity after mTBI. Behavioral assessment of the same cohort of animals prior to fLDI showed that mTBI resulted in persistent contralateral sensorimotor behavioral deficit along with ipsilateral neuronal loss compared to sham. Treating mTBI rats with Kaempferol, a dietary flavonol compound that enhanced mitochondrial Ca2+ uptake, eliminated the inter-hemispheric asymmetry in the whisker stimulation-induced positive CBF responses and the ipsilateral negative CBF responses otherwise observed in the untreated and vehicle-treated mTBI animals in adulthood. Kaempferol also improved somatosensory behavioral measures compared to untreated and vehicle treated mTBI animals without augmenting post-injury neuronal loss. The results indicate that reduced mitochondrial Ca2+ uptake in the surviving populations affect post-traumatic neural activation leading to persistent behavioral deficits. Improvement in sensorimotor behavior and spatiotemporal neurovascular activity following kaempferol treatment suggests that facilitation of mitochondrial Ca2+ uptake in the early window after injury may sustain optimal neural activity and metabolism and contribute to improved function of the surviving cellular populations after mTBI.

Potential immunotherapies for traumatic brain and spinal cord injury

“…The secondary injury contributes largely to the neurological impairment seen in patients. Several mechanisms underlying the secondary injury have been identified: excitotoxicity caused by impaired glutamate homeostasis, 8 , 9 free radicals/oxidative stress/lipid peroxidation, 10 , 11 calcium overload, 12 , 13 autophagy, 14 and sterile neuroinflammation. 15 Recently, the sequential activation of resident and recruited immune cells has been extensively investigated for their participation in the secondary inflammatory/immune responses after CNS injury.…”

Beneficial Effects of Kaempferol after Developmental Traumatic Brain Injury Is through Protection of Mitochondrial Function, Oxidative Metabolism, and Neural Viability

“…The WSIMR behavior in the current untreated and vehicle treated TBI animals was reproducible and comparable to that of our previous studies on this developmental TBI model. 27 Kaempferol treated TBI animals showed significantly improved ipsilateral ( Fig. 2A) and contralateral WSIMR scores (Fig.…”

“…37 We have modified this sensorimotor test successfully to developmental stage animals as established by our previous studies. 16,27 Animals were placed in a test cage and left to habituate for 1 min. Subsequently, whiskers on either side were stroked in a rostrocaudal direction using an applicator stick.…”

“…24,25 In a pre-clinical rat model of TBI, treatment with intraperitoneal kaempferol (1 mg/kg) during the acute/subacute stage (0-72 h after TBI) in three doses separated by 24 h, significantly improved the long-term behavioral and brain function assessed two months post-TBI. 27 We hypothesized that the protective action of kaempferol after TBI was through a mitochondrial mechanism of action. Based on the broad metabolomic impact of developmental TBI determined previously, 16 we examined the effects of kaempferol treatment on the TBI metabolome to test the mechanism of action of kaempferol.…”

Microglia dynamics in adolescent traumatic brain injury

“…Secondary injury cascades can initiate within minutes of injury and extend for months. They are characterized by dysregulated cerebral blood flow (CBF) [ 63 ], altered metabolic and cellular homeostasis, ionic dysregulation [ 64 ], mitochondrial dysfunction [ 65 ], neuronal atrophy, cell death, and neuroinflammation [ 66 ] (Fig. 1 b).…”