Inhibition of P2X7 receptors improves outcomes after traumatic brain injury in rats

Abstract

Traumatic brain injury (TBI) is the leading cause of death and disability for people under the age of 45 years worldwide. Neuropathology after TBI is the result of both the immediate impact injury and secondary injury mechanisms. Secondary injury is the result of cascade events, including glutamate excitotoxicity, calcium overloading, free radical generation, and neuroinflammation, ultimately leading to brain cell death. In this study, the P2X7 receptor (P2X7R) was detected predominately in microglia of the cerebral cortex and was up-regulated on microglial cells after TBI. The microglia transformed into amoeba-like and discharged many microvesicle (MV)-like particles in the injured and adjacent regions. A P2X7R antagonist (A804598) and an immune inhibitor (FTY720) reduced significantly the number of MVlike particles in the injured/adjacent regions and in cerebrospinal fluid, reduced the number of neurons undergoing apoptotic cell death, and increased the survival of neurons in the cerebral cortex injured and adjacent regions. Blockade of the P2X7R and FTY720 reduced interleukin-1βexpression, P38 phosphorylation, and glial activation in the cerebral cortex and improved neurobehavioral outcomes after TBI. These data indicate that MV-like particles discharged by microglia after TBI may be involved in the development of local inflammation and secondary nerve cell injury.

P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

“…These findings were confirmed for the rat spinal cord [ 65 ] and extended for the rat parietal cortex [ 66 ]. Whereas in the former study BBG was used as a P2X7R antagonist, in the latter study the P2X7R antagonist A-804598 of higher selectivity was utilized.…”

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

“…This inflammasome complex allows the cleavage of pro-caspase-1 into its active isomer, caspase-1, which in turn cleaves pro-IL-1β and pro-IL-18 to their active isomers IL-1β and IL-18 respectively. The increase in these pro-inflammatory proteins ultimately leads to pyroptosis neurons has been disputed, its expression has consistently been found in microglia and astrocytes [59][60][61]. As such, NLRP3 activity is receiving growing interest as a contributor to various CNS conditions in which gliamediated neuroinflammation has been associated with disease progression such as Alzheimer's disease, stroke, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and pneumococcal meningitis [62][63][64][65][66][67][68].…”

“…Although further studies are required, taken together these pharmacological studies have further established the link between the NLRP3 inflammasome and TBI, and suggest that treatments target this pathway may have potential for improving TBI outcomes. In particular, given that astrocyte and microglia reactivity can be prominent following TBI [14][15][16][17], and these cell types are the primary cells that express NLRP3 [59,70], it is hypothesized that NLRP3-associated molecules may have utility as biomarkers of TBI pathophysiology. While few studies have investigated serum levels of NLRP3 inflammasome-related proteins in the context of neuroinflammatory conditions, protein levels of ASC, caspase-1, IL-1β, and IL-18 were all found to be significantly upregulated in the serum of ischemic stroke patients compared to age-matched healthy controls [103].…”

The role of convergent ion channel pathways in microglial phenotypes: a systematic review of the implications for neurological and psychiatric disorders

“…2 h post insult then 22.5 mg/kg i.p. every 24 h until day 9 10 days after the insult Iba-1 Corpus callosum, cingulum ↑ ↓ k-atp channel Ortega et al 2012 26 MCAo 15/group Glibenclamide 6, 12, and 24 h after reperfusion 0.06 or 0.6 or 6 mcg 72 h after MCAo IB4 Subcortical and cortical region ↑ ----- P2Y12 Gelosa et al 2014 26 MCAo 6/group Ticagrelor 10 min, and then 22 and 36 h after MCAo 3 mg/Kg or 30 mg/Kg 2 h after MCAo Iba-1 and ED-1 Dorsal and ventral areas ↑ ↓ TBI P2X7 Liu et al 2017 28 Modified weight drop technique 6/group A804598 5 days A804598: 10 mg/Kg 6,12, 24 h Iba-1 Cortex ↑ ↓ Spinal cord injury P2X4 Zhou et al 2014 29 Method of Decosterd and Woolf 4/group Dexmedetomidine 14 days 40 mcg/kg 1, 3, 5, 7, 14 h after surgery Iba-1 Spinal cord ↑ ↓ Pain P2X7 He et al 2012 30 Chronic constriction injury model 7/group BBG 14 days 10 mcl 14 days after nerve injury OX-42 Spinal cord ↑ ↓ Parkinson P2X7 Wang et al 2017 31 LPS injected to the right substantia nigra 12 × 6 BBG 15 days 50 mg/ Kg 15 days Iba-1 ...…”

“…There was only one study evaluating P2X7 blockade and microglial activation in traumatic brain injury (TBI) 28 . According to the study, purinergic antagonism attenuated microglial activated state and improved neurobehavioral outcomes after TBI.…”