Exogenous Administration of PACAP Alleviates Traumatic Brain Injury in Rats through a Mechanism Involving the TLR4/MyD88/NF-κB Pathway

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is effective in reducing axonal damage associated with traumatic brain injury (TBI), and has immunomodulatory properties. Toll-like receptor 4 (TLR4) is an important mediator of the innate immune response. It significantly contributes to neuroinflammation induced by brain injury. However, it remains unknown whether exogenous PACAP can modulate TBI through the TLR4/adapter protein myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway. In this study, we investigated the potential neuroprotective mechanisms of PACAP pretreatment in a weight-drop model of TBI. PACAP38 was microinjected intracerebroventricularly before TBI. Brain samples were extracted from the pericontusional area in the cortex and hippocampus. We found that TBI induced significant upregulation of TLR4, with peak expression occurring 24 h post-trauma, and that pretreatment with PACAP significantly improved motor and cognitive dysfunction, attenuated neuronal apoptosis, and decreased brain edema. Pretreatment with PACAP inhibited upregulation of TLR4 and its downstream signaling molecules MyD88, p-IκB, and NF-κB, and suppressed increases in the levels of the downstream inflammatory agents interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), in the brain tissue around the injured cortex and in the hippocampus. Administration of PACAP both in vitro and in vivo attenuated the ability of the TLR4 agonist lipopolysaccharide (LPS) to increase TLR4 protein levels. Therefore, PACAP exerts a neuroprotective effect in this rat model of TBI, by inhibiting a secondary inflammatory response mediated by the TLR4/MyD88/NF-κB signaling pathway in microglia and neurons, thereby reducing neuronal death and improving the outcome following TBI.

Activation of BV2 microglia by lipopolysaccharide triggers an inflammatory reaction in PC12 cell apoptosis through a toll-like receptor 4-dependent pathway

“…Proinflammatory cytokines as neurotoxic factors can cause neuronal damage. Our previous studies both in vitro and in vivo verified that TLR4/MyD88/NF-κB signaling pathway was involved in the neuroinflammatory response and innate immune response in microglia under traumatic brain injury and glucose deprivation/ reoxygenation (Mao et al 2012;Qin et al 2012).…”

“…NF-κB plays a wellcharacterized role in regulating cytokine production. Our previous studies found that TLR4/MyD88 signaling pathway was involved in traumatic brain injury in vivo (Mao et al 2012), BV2 microglia injury following the oxygen and glucose deprivation (OGD)/reoxygenation in vitro (Bechade et al 2013;Qin et al 2013), and digestive diseases (De Paola et al 2012). The TLR4-activated downstream signaling pathway, including MyD88 activation and NF-κB translocation, could promote microglia activation and the production of proinflammatory cytokines.…”

“…Activation of microglia is interpreted as an inflammatory response to infection, and microglia cytokines are known to induce neuronal death in models of neurodegeneration (Tanga et al 2005). Our group reported that TLR4 /MyD88 signaling pathway is involved in traumatic brain injury (Mao et al 2012). In vitro studies, with microglia co-cultured with neurons, Schisandrin B may exert neuroprotective activity by attenuating the microglia-mediated neuroinflammatory response by inhibiting the TLR4/MyD88/NF-κB signaling pathway (Zeng et al 2012).…”

“…Over the last decade, a rapidly growing body of evidence indicated that microglia, as the representative of immune cells in CNS, play important roles in neuropathic disease (Schulz 2007;Suter et al 2007). Activated microglia are involved in various CNS diseases, such as pain (Baron 2006;Inoue and Tsuda 2009;Smith 2010;Tsuda et al 2012), infection (Lehnardt 2010), neurodegeneration, brain trauma (Mao et al 2012), stroke, and any real or potential danger to the CNS (Aravalli et al 2007).…”

Advances in diagnosis, treatments, and molecular mechanistic studies of traumatic brain injury

“…An anti-seizure drug may be given during the first week to avoid any additional brain damage that might be caused by a seizure. Additional anti-seizure the up-regulation of NF-κB in brain tissue (47,50,51).…”