Neuroinflammatory Cytokine Response, Neuronal Death and Microglial Proliferation in the Hippocampus of Rats During the Early Period After Lateral Fluid-Percussion-Induced Traumatic Injury of the Neocortex

Time course of changes in neuroinflammatory processes in the dorsal and ventral hippocampus was studied during the early period after lateral fluid-percussion-induced neocortical traumatic brain injury (TBI) in the ipsilateral and contralateral hemispheres. In the ipsilateral hippocampus, neuroinflammation (increase in expression of pro-inflammatory cytokines) was evident from day 1 after TBI and ceased by day 14, while in the contralateral hippocampus it was mainly limited to the dorsal part on day 1. TBI induced an increase in hippocampal corticosterone level on day 3 bilaterally and an accumulation of Il1b on day 1 in the ipsilateral hippocampus. Activation of microglia was observed from day 7 in different hippocampal areas of both hemispheres. Neuronal cell loss was detected in the ipsilateral dentate gyrus on day 3 and extended to the contralateral hippocampus by day 7 after TBI. The data suggest that TBI results in distant hippocampal damage (delayed neurodegeneration in the dentate gyrus and microglia proliferation in both the ipsilateral and contralateral hippocampus), the time course of this damage being different from that of the neuroinflammatory response.

Neuroinflammatory Cytokine Response, Neuronal Death and Microglial Proliferation in the Hippocampus of Rats During the Early Period After Lateral Fluid-Percussion-Induced Traumatic Injury of the Neocortex

Time course of changes in neuroinflammatory processes in the dorsal and ventral hippocampus was studied during the early period after lateral fluid-percussion-induced neocortical traumatic brain injury (TBI) in the ipsilateral and contralateral hemispheres. In the ipsilateral hippocampus, neuroinflammation (increase in expression of pro-inflammatory cytokines) was evident from day 1 after TBI and ceased by day 14, while in the contralateral hippocampus it was mainly limited to the dorsal part on day 1. TBI induced an increase in hippocampal corticosterone level on day 3 bilaterally and an accumulation of Il1b on day 1 in the ipsilateral hippocampus. Activation of microglia was observed from day 7 in different hippocampal areas of both hemispheres. Neuronal cell loss was detected in the ipsilateral dentate gyrus on day 3 and extended to the contralateral hippocampus by day 7 after TBI. The data suggest that TBI results in distant hippocampal damage (delayed neurodegeneration in the dentate gyrus and microglia proliferation in both the ipsilateral and contralateral hippocampus), the time course of this damage being different from that of the neuroinflammatory response.

Molecular Targeting of Nrf2 and NFkB Signaling by 3-acetyl-11-keto- β-boswellic Acid and Piperine in Fluid Percussion Rat Model of Traumatic Brain Injury

Background & purpose: Traumatic brain injury in rats through lateral fluid percussion injury (LFPI) causes elevation in intracranial pressure which leads to impairments in motor and cognitive behavior. 3-acetyl-11-keto-β-boswellic acid (AKBA) is a well-known anti-inflammatory agent but it has very low bioavailability. The current study was established to investigate the neuroprotective effect of AKBA in combination with bioenhancer piperine in LFPI induced TBI experimental rats.Experimental approach: Fluid percussion injury was created by delivering 50 mmHg of pressure for 3 minutes to the exposed brain. AKBA 25 mg/kg and 50 mg/kg orally and AKBA ((25 mg/kg, p.o.) in combination with piperine (2.5 mg/kg, p.o.) was administered from day 1 to day 14. On 1st, 7th and 14th day, the behavioral parameters were checked. On 15th day, animals were euthanized. Then the cortex was isolated for the estimation of biochemical levels (MDA, nitrite, reduced GSH, catalase), neuroinflammatory markers (TNF-α, IL-1β, IL-6), and neurotransmitters (norepinephrine, dopamine, 5-HT, GABA, glutamate). From some animals, hippocampus and cortex were isolated for histopathological analysis and expressions of Nrf2 and NFkB was measured by immunohistological study. Key results: Treatment with AKBA significantly attenuated LFPI induced abnormalities, biochemical and neurotransmitter changes in experimental rats. Further finding AKBA in combination with piperine significantly prevented histopathological changes, increased Nrf2 positive cells and reduced NFkB expression in the cortical region. Conclusion & implication: The present study concluded that AKBA along with piperine achieved anti-oxidant, anti-inflammatory, neuromodulatory effects as well as prevented neuronal injury via targeting Nrf2 and NFkB.

Transcriptional Pathology Evolves Over Time in Rat Hippocampus Following Lateral Fluid Percussion Traumatic Brain Injury

Traumatic brain injury (TBI) causes acute and lasting impacts on the brain, driving pathology along anatomical, cellular, and behavioral dimensions. Rodent models offer the opportunity to study TBI in a controlled setting, and enable analysis of the temporal progression that occurs from injury to recovery. We applied transcriptomic and epigenomic analysis, characterize gene expression and in ipsilateral hippocampus at 1 and 14 days following moderate lateral fluid percussion (LFP) injury. This approach enabled us to identify differential gene expression (DEG) modules with distinct expression trajectories across the two time points. The major DEG modules represented genes that were up- or downregulated acutely, but largely recovered by 14 days. As expected, DEG modules with acute upregulation were associated with cell death and astrocytosis. Interestingly, acutely downregulated DEGs related to neurotransmission mostly recovered by two weeks. Upregulated DEG modules related to inflammation were not necessarily elevated acutely, but were strongly upregulated after two weeks. We identified a smaller DEG module with delayed upregulation at 14 days including genes related to cholesterol metabolism and amyloid beta clearance. Finally, differential expression was paralleled by changes in H3K4me3 at the promoters of differentially expressed genes at one day following TBI. Following TBI, changes in cell viability, function and ultimately behavior are dynamic processes. Our results show how transcriptomics in the preclinical setting has the potential to identify biomarkers for injury severity and/or recovery, to identify potential therapeutic targets, and, in the future, to evaluate efficacy of an intervention beyond measures of cell death or spatial learning.