Poloxamer-188 Attenuates TBI-Induced Blood–Brain Barrier Damage Leading to Decreased Brain Edema and Reduced Cellular Death

Abstract

Plasmalemma permeability plays an important role in the secondary neuronal death induced by traumatic brain injury (TBI). Previous works showed that Poloxamer 188 (P188) could restore the intactness of the plasma membrane and play a cytoprotective action. However, the roles of P188 in blood-brain barrier (BBB) integrity and TBI-induced neural cell death are still not clear. In this study, mice were induced TBI by controlled cortical impact (CCI), and cerebral water content was measured to explore the profile of brain edema after CCI. Further, the regimen of P188 in mouse CCI models was optimized. The neurological test and BBB integrity assessment were performed, and the numbers of TBI-induced neural cell death were counted by propidium iodide (PI) labeling. The expression of apoptotic pathway associated proteins (Bax, cyt-c, caspase-8, caspase-9, caspase-3, P53) and aquaporin-4 (AQP4) was assessed by RT-PCR or immunoblotting. The data showed that the brain edema peaked at 24 h after TBI in untreated animals. Tail intravenous injection of P188 (4 mg/ml, 100 μl) 30 min before TBI or within 30 min after TBI could attenuate TBI-induced brain edema. P188 pre-treatment restored BBB integrity, suppressed TBI-induced neural cell death, and improved neurological function. TBI induced an up-regulation of Bax, cyt-c, caspase-8, caspase-9, caspase-3, and the expression of p53 was down-regulated by P188 pre-treatment. AQP4 mainly located on endothelial cells and astrocytes, and its expression was also regulated by P188 pretreatment. All these results revealed that P188 attenuates TBI-induced brain edema by resealing BBB and regulating AQP4 expression, and suppressed apoptosis through extrinsic or intrinsic pathway. Plasmalemma permeability may be a potential target for TBI treatment.

Inhibition of Lats1/p‐YAP1 pathway mitigates neuronal apoptosis and neurological deficits in a rat model of traumatic brain injury

“…Throughout the previous studies, except apoptosis, TBI is often accompanied by many other events such as brain edema, destruction of BBB permeability, and neurological impairment . Our data also show that the destruction of the BBB permeability impaired following TBI (Figure S1).…”

Protective Effects of Ginsenoside Rg1 on Astrocytes and Cerebral Ischemic-Reperfusion Mice

“…Previous studies have demonstrated that aquaporin-4 (AQP4) is implicated in the formation and resolution of brain edema, which is one important consequence of cerebral ischemia. [31][32][33][34] Zeng et al 35) found that 10% hypertonic saline exerted anti-edema effects possibly through downregulation of AQP4 expression in the perivascular astrocytes. Hua et al 36) also found that AQP4 played an important role in modulating brain water transport in an astrocytic oxygen-glucose deprivation and reintroduction model.…”

PEO–PPO Diblock Copolymers Protect Myoblasts from Hypo-Osmotic Stress In Vitro Dependent on Copolymer Size, Composition, and Architecture

“…P188 reduced infarct volume, motor deficits, and death after ischemia/reperfusion in mice 17 ; improved recovery to myocardial infarction 18 and cardiac arrest in pigs; 19 prolonged survival and reduced tissue damage upon hypotensive resuscitation in rats; 20 and enhanced survival time after severe hemorrhage in pigs. 21 In mice, P188 reduced intracerebral hemorrhage injury volume and reduced neurological symptoms; 22 improved blood-brain barrier integrity after traumatic brain injury; 23 and resealed cells in the cortex and hippocampus after controlled cortical impact. 24 In culture, P188 reduced necrosis and apoptosis 25 as well as improved viability, reduced enzyme leakage, and improved integrity of mitochondrial and lysosomal membranes following mechanical stress or ischemia.…”