Dexmedetomidine Attenuates Neuroinflammatory–Induced Apoptosis after Traumatic Brain Injury via Nrf2 signaling pathway

Abstract

Objective Dexmedetomidine (DEX) exhibits neuroprotective effects as a multifunctional neuroprotective agent in numerous neurological disorders. However, in traumatic brain injury (TBI), the molecular mechanisms of these neuroprotective effects remain unclear. The present study investigated whether DEX, which has been reported to exert protective effects against TBI, could attenuate neuroinflammatory‐induced apoptosis and clarified the underlying mechanisms. Methods A weight‐drop model was established, and DEX was intraperitoneally injected 30 min after inducing TBI in rats. The water content in the brain tissue was measured. Terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling (TUNEL) assays were performed on histopathological tissue sections to evaluate neuronal apoptosis. Enzyme‐linked immunosorbent assay and PCR were applied to detect the levels of the inflammatory factors, TNF‐α, IL‐1β, IL‐6, and NF‐κB. Results TBI–challenged rats exhibited significant neuronal apoptosis, which was characterized via the wet‐to‐dry weight ratio, neurobehavioral functions, TUNEL assay results and the levels of cleaved caspase‐3, Bax upregulation and Bcl‐2, which were attenuated by DEX. Western blot, immunohistochemistry, and PCR results revealed that DEX promoted Nrf2 expression and upregulated expression of the Nrf2 downstream factors, HO‐1 and NQO‐1. Furthermore, DEX treatment markedly prevented the downregulation of inflammatory response factors, TNF‐α, IL‐1β and NF‐κB, and IL‐6. Interpretation Administering DEX attenuated inflammation‐induced brain injury in a TBI model, potentially via the Nrf2 signaling pathway.

Cerebrovascular and neurological impact of chronic smoking on post traumatic brain injury outcome and recovery: an in vivo study

“…Our in vivo data that the Nrf2-ARE system gets activated in response to TBI (see Fig. 6) This effect could be due to a direct modulatory activity toward Nrf2 expression and activation of the Nrf2-ARE pathway in response to trauma and are in line with the results obtained in a previous study by Li et al indicating significantly enhanced Nrf2, NQO-1 and HO-1 protein expression following TBI (44). However, chronic TS exposure as a stand-alone stimulus has the opposite effect (see Fig.…”

“…According to recent studies, while suppression of Nrf2 activity and impairments of the Nrf2-ARE pathway exacerbate TBI-induced oxidative damage as well as post-traumatic neurological deficits, NRF2 played a significant neuroprotective role in TBI and neurodegenerative disorders (4,11). Since the upregulation of Nrf2 activity ameliorates TBI-induced brain injury it could be suggested that positive modulation of Nrf2 could better TBI outcomes through reduction of oxidative stress, inflammation, and protection of BBB integrity (23,24,(41)(42)(43)(44)(45).…”

Nrf2/HO-1 mediates neuroprotective effects of pramipexole by attenuating oxidative damage and mitochondrial perturbation after traumatic brain injury

“…Nrf2 is a transcription factor that is associated with Kelch-like ECH-associated protein-1 (Keap1) in the cytosol. During stress or other pathological conditions, Nrf2 dissociates from Keap1 and translocates to the nucleus, where it activates various antioxidant genes and phase II enzymes such as HO-1 and NQO-1 by binding with an ARE, and reduces the oxidative stress and inflammatory response involved in the acute brain injury following a TBI ( Li et al, 2019b ).…”

“…Nuclear factor erythroid 2-related factor-2 (Nrf2; also known as Nfe2l2) is a transcription factor and important upregulator of the endogenous cell defense mechanism in response to oxidative damage and is involved in restoration of intracellular homeostasis ( Li et al, 2019b ). Nrf2 is a basic leucine zipper (bZIP) cytoplasmic protein, which translocates into the nucleus under oxidative stress.…”

Dexmedetomidine alleviates inflammation-induced neuropathic pain by suppressing NLRP3 via activation of Nrf2

“…A recent study claimed that DEX exerted neuroprotective effect via Nrf2 signaling pathway [17]. The present research utilizes NLRP3 antagonist MCC950, NLRP3 activator Nigericin and Nrf2 inhibitor ML385…”