Abstract
Decompressive craniectomy is an effective strategy to reduce intracranial hypertension after traumatic brain injury (TBI), but it is related to many postoperative complications, such as delayed intracranial hematoma and diffuse brain swelling. Our previous studies have demonstrated that controlled decompression (CDC) surgery attenuates brain injury and reduces the rate of complications after TBI. Here, we investigated the potential molecular mechanisms of CDC in experimental models. The in vitro experiments were performed in a traumatic neuronal injury (TNI) model following compression treatment in primary cultured cortical neurons. We found that compression aggravates TNI-induced neuronal injury, which was significantly attenuated by CDC for 2 h or 3 h. The results of immunocytochemistry showed that CDC reduced neuronal necroptosis and activation of RIP3 induced by TNI and compression, with no effect on RIP1 activity. These protective effects were associated with decreased levels of inflammatory cytokines and preserved intracellular Ca2+ homeostasis. In addition, the expression of the two-pore domain K+ channel TREK-1 and its activity was increased by compression and prolonged by CDC. Treatment with the TREK-1 blockers, spadin or SID1900, could partially prevent the effects of CDC on intracellular Ca2+ metabolism, necroptosis, and neuronal injury following TNI and compression. Using a traumatic intracranial hypertension model in rats, we found that CDC for 20 min or 30 min was effective in alleviating brain edema and locomotor impairment in vivo. CDC significantly inhibited neuronal necroptosis and neuroinflammation and increased TREK-1 activation, and the CDC-induced protection in vivo was attenuated by spadin and SID1900. In summary, CDC is effective in alleviating compressive neuronal injury both in vitro and in vivo, which is associated with the TREK-1-mediated attenuation of intracellular Ca2+ overload, neuronal necroptosis, and neuroinflammation.
Highlights
Traumatic brain injury (TBI) has been considered as one of the most complex human diseases because of the complexity of brain damage mechanisms and poor prognosis
We performed immunostaining using the TREK-1 antibody in brain sections after traumatic intracranial hypertension (Figure 3(a)), and the results showed that rapid decompression group (RDC) and controlled decompression (CDC) both increased the expression of TREK-1 with the higher levels of TREK-1 in the CDC group (Figure 4(b))
We found that (a) CDC (2 h and 3 h) effectively reduces compressive neuronal damage following traumatic neuronal injury (TNI), (b) CDC significantly inhibits neuronal necrosis and RIP3 activation;,(c) CDC markedly decreases the levels of inflammatory cytokines, (d) compression-induced intracellular Ca2+ overload is Without spadin Spadin Control (a) TNI+compression
Summary
Traumatic brain injury (TBI) has been considered as one of the most complex human diseases because of the complexity of brain damage mechanisms and poor prognosis. Our previous studies have demonstrated that the controlled decompression (CDC) surgery attenuates brain injury and reduces the rates of complications after TBI [4,5,6]. In the central nervous system (CNS), a variety of cellular physiological processes, including neurotransmitter release, neuronal excitability, and plasticity, are regulated by ion channels, especially Ca2+ and K+ ions [7]. The tandem of pore domain in weak inwardly rectifying K+ channel- (TWIK-) related K+ channels (TREK) belongs to the recently discovered two-pore domain K+ (K2P) channels, which include 15 members grouped in six subfamilies and are responsible for Oxidative Medicine and Cellular Longevity maintaining the neuronal resting membrane potential [8]. TREK-1 is located at both presynaptic and postsynaptic components, which are its key roles in maintaining the resting membrane potential and neurotransmitter release. The role of TREK-1 in traumatic intracranial hypertension conditions has not been fully determined
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