Astaxanthin alleviates cerebral edema by modulating NKCC1 and AQP4 expression after traumatic brain injury in mice

Abstract

BackgroundAstaxanthin is a carotenoid pigment that possesses potent antioxidative, anti-inflammatory, antitumor, and immunomodulatory activities. Previous studies have demonstrated that astaxanthin displays potential neuroprotective properties for the treatment of central nervous system diseases, such as ischemic brain injury and subarachnoid hemorrhage. This study explored whether astaxanthin is neuroprotective and ameliorates neurological deficits following traumatic brain injury (TBI).ResultsOur results showed that, following CCI, treatment with astaxanthin compared to vehicle ameliorated neurologic dysfunctions after day 3 and alleviated cerebral edema and Evans blue extravasation at 24 h (p < 0.05). Astaxanthin treatment decreased AQP4 and NKCC1 mRNA levels in a dose-dependent manner at 24 h. AQP4 and NKCC1 protein expressions in the peri-contusional cortex were significantly reduced by astaxanthin at 24 h (p < 0.05). Furthermore, we also found that bumetanide (BU), an inhibitor of NKCC1, inhibited trauma-induced AQP4 upregulation (p < 0.05).ConclusionsOur data suggest that astaxanthin reduces TBI-related injury in brain tissue by ameliorating AQP4/NKCC1-mediated cerebral edema and that NKCC1 contributes to the upregulation of AQP4 after TBI.

Antioxidant Therapies in Traumatic Brain Injury

“…In a stretch injury model of TBI using astrocyte cultures, astaxanthin attenuated apoptosis by inhibiting NKCC1 expression, and reduced the expression of NF-κB-mediated pro-inflammatory factors [103]. In mice, intraperitoneal injection of astaxanthin (10,25,50, or 100 mg/kg body weight) administrated 30 min after impact, decreased TBI-related brain tissue injury (induced by CCI) by dose-dependently ameliorating AQP4/NKCC1-mediated cerebral edema.…”

A Precision Medicine Approach to Cerebral Edema and Intracranial Hypertension after Severe Traumatic Brain Injury: Quo Vadis?

“…In non-TBI models limited primarily to cytotoxic edema (such as water intoxication), AQP4−/− mice have reduced edema; however, in models with predominantly vasogenic edema (tumors, subarachnoid hemorrhage, abscess), there is worsening of edema [92, 113, 114] potentially consistent with the aforementioned importance of AQP4 in water elimination [81, 95, 96]. There are isolated reports of pharmacologic AQP4 inhibition showing benefit on edema reduction in TBI with multiple compounds via different mechanisms including AER-271, astaxanthin, ghrelin, and propofol that warrant further exploration in corroboratory preclinical work prior to translation to humans [115-119]. …”

“…NKCC1 is rapidly upregulated after preclinical TBI (within 1 h), resulting in cellular swelling due to increased ion and water influx and reduced efflux. In animal models, the upregulation and contribution of NKCC1 to both cytotoxic and vasogenic edema are connected with other pathways including glutamate, IL-1β,MMP-9, and AQP4[115,178,192-196]. …”

CT‐Based Classification of Acute Cerebral Edema: Association with Intracranial Pressure and Outcome

“…Among the 31 patients with focal edema (grade 1-3), only 3 patients died, and 12 achieved a favorable outcome . Outcome of patients with TBI n = 14 Contusion (9) Subdural (9) Subarachnoid (12) Moderate 3Severe (11) Frontal (9) Temporal 7Parietal 3Yes ( 4none 2VA 1Clip (13) Coil 11None 29.0/2.0 3/0.5…”

“…11 Animal models can measure brain edema as water content 12 and BBB disruption using Evans blue dye extravasation. 13 In clinical studies, monitoring the extent of edema formation on CT scans can be used and for ICP management, this technique has been shown to be feasible as a guide for antiedematous therapy management. 14 However, in clinical practice ICPvalues are overwhelmingly used for monitoring and management of therapy of elevated intracranial pressure.…”