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Common molecular signature of two neuroprotective agents

ABSTRACT: The current lack of proven pharmacological treatment options for traumatic brain injury (TBI) patients reflects the poor translation of successful preclinical studies in clinical trials. This may be due to poor choice of therapeutic agents based on incomplete knowledge of critical elements of neuroprotection. Our goal is to expedite discovery and translation of therapeutic agents that can improve functional outcome by identifying the common molecular profile of neuroprotective drugs. Since damage to the hippocampus is associated with TBI-induced deficits in learning and memory, we analyzed of the hippocampal transcriptional profiles of TBI rats treated with two clinically used drugs metyrapone and carbenoxolone, which have been shown to improve cognitive deficits in previous studies. Despite their different structures, we found that MT and CB have similar effects on several known biological pathways. The neuroprotective effects of these drugs are associated with a distinctive molecular signature which is characterized not by changes in expression of any individual gene but by a common global effect on multiple cell signaling pathways. These data suggest that drug treatments that induce a coordinated attenuation of multiple injury-induced cell signaling networks, both deleterious and protective, have high translational potential.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE31357 | GEO | 2012/12/23

SECONDARY ACCESSION(S): PRJNA145945

REPOSITORIES: GEO

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Common molecular signature of two neuroprotective agents

Project description:The current lack of proven pharmacological treatment options for traumatic brain injury (TBI) patients reflects the poor translation of successful preclinical studies in clinical trials. This may be due to poor choice of therapeutic agents based on incomplete knowledge of critical elements of neuroprotection. Our goal is to expedite discovery and translation of therapeutic agents that can improve functional outcome by identifying the common molecular profile of neuroprotective drugs. Since damage to the hippocampus is associated with TBI-induced deficits in learning and memory, we analyzed of the hippocampal transcriptional profiles of TBI rats treated with two clinically used drugs metyrapone and carbenoxolone, which have been shown to improve cognitive deficits in previous studies. Despite their different structures, we found that MT and CB have similar effects on several known biological pathways. The neuroprotective effects of these drugs are associated with a distinctive molecular signature which is characterized not by changes in expression of any individual gene but by a common global effect on multiple cell signaling pathways. These data suggest that drug treatments that induce a coordinated attenuation of multiple injury-induced cell signaling networks, both deleterious and protective, have high translational potential. There were 16 samples for array analysis, two biological replicates each for control (4 and 24 hour), TBI (4 and 24 hour), TBI plus MT (4 and 24 hour) and TBI plus CB (4 and 24 hour). Each biological sample, which is a pooled RNA sample (laser captured CA3 pyramidal neurons) from the hippocampus of 3-6 rats, was hybridized to duplicate arrays so that there were 32 gene arrays in this study.

2012-12-23 | E-GEOD-31357 | biostudies-arrayexpress

miRNA expression of whole hippocampus 24hr post-injury in rat

Project description:Traumatic brain injury dysregulates microRNA expression in the brain. We hypothesized that injury-induced epigenetic changes contribute to neurodegeneration and learning and memory deficits after TBI. These changes may provide a mechanistic explanation for neuropsychiatric comorbidities in TBI patients. Our objective is to compare and contrast the effects of several neuroprotective drugs (JM6, PMI-006 and E33-estrogen) on the TBI-induced changes in microRNA expression in the hippocampus, a region of the brain that is critical for learning and memory. We will also study if different neuroprotective drugs have similar effects on common microRNAs which may cooperatively regulate a common set of gene targets. 3 biological samples each of NaÃ¯ve, Sham control, TBI and TBI plus JM6, TI plus PMI-006, and TBI plus E33 rat hippocampi were obtained 24 hr post-sham injury or TBI, stored in RNA later and sent to GenUs Biosystems for microRNA microarray analysis.

2015-01-08 | E-GEOD-59646 | biostudies-arrayexpress

Gene expression of whole hippocampus 24hr post-injury in rat

Project description:Traumatic brain injury (TBI) alters and dysregulates the expression of thousands of genes in the brain. Since some of the most common problems in TBI patients are learning and memory deficits, we are studying the effects of TBI on the hippocampus, a region of the brain which is essential for learning and memory and which is known to be particularly vulnerable to TBI. We are interested in understanding how potential neuroprotective drugs alter the TBI-induced gene expression profile. The objective of this study is to elucidate and compare the differential gene expression profiles in the hippocampus of naive, sham-control, TBI and TBI plus drug treated rats. JM6, PMI-006 and E33 are three compounds with neuroprotective, anti-inflammatory and anti-oxidative effects. Our goal is to determine if different neuroprotective compounds have similar effects on common gene targets. These genes and the cell signaling pathways linked to them would then be the target of new therapeutic strategies for TBI. Rats were prepared for fluid percussion traumatic brain injury or sham injury (naÃ¯ve rats had no anesthesia and were not handled in any way and gene expression in their brains serve as baseline data) and 24 hr post-injury, hippocampi were obtained, and stored in RNA later. Total RNA was isolated, quantitified and used for Agilent microarray analysis at GenUs Biosystems. Each group of naive, sham control, TBI and TBI plus JM6, TBI plus PMI-006 and TBI plus E33 (estrogen) has three biological replicates.

2015-01-08 | E-GEOD-59645 | biostudies-arrayexpress

miRNA expression of whole hippocampus 24hr post-injury in rat

2015-01-08 | GSE59646 | GEO

Gene expression of whole hippocampus 24hr post-injury in rat

2015-01-08 | GSE59645 | GEO

Blast traumatic brain injury induced cognitive deficits are attenuated by pre- or post-injury treatment with the glucagon-like peptide-1 receptor agonist, exendin-4 [Day 3 dataset]

Project description:Blast traumatic brain injury (B-TBI) affects military and civilian personnel. Presently there are no approved drugs for blast brain injury. Exendin-4, administered subcutaneously, was evaluated as a pre-treatment (48 hours) and post-injury treatment (2 hours) on neurodegeneration, behaviors and gene expressions in a murine open field model of blast injury. B-TBI induced neurodegeneration, changes in cognition and genes expressions linked to dementia disorders. Exendin-4, administered pre- or post-injury ameliorated B-TBI-induced neurodegeneration at 72 hours, memory deficits from days 7-14 and attenuated genes regulated by blast at day 14 post-injury. The present data suggest shared pathological processes between concussive and B-TBI, with endpoints amenable to beneficial therapeutic manipulation by exendin-4. B-TBI-induced dementia-related gene pathways and cognitive deficits in mice somewhat parallel epidemiological studies of Barnes and co-workers who identified a greater risk in US military veterans who experienced diverse TBIs, for dementia in later life.

2016-08-05 | GSE71846 | GEO

Proteomics characterization of the neuroprotective effects of low-dose methamphetamine on rats with traumatic brain injury (TBI)

Project description:Traumatic brain injury (TBI) causes hospitalizations and mortality worldwide with no approved neuroprotective treatments available, partly due to a poor understanding of the molecular mechanisms underlying TBI neuropathology and neuroprotection. We previously reported that the administration of low-dose methamphetamine (MA) induced significant functional/cognitive improvements following severe TBI in rats. We further demonstrated that MA mediates neuroprotection in part, via dopamine-dependent activation of the PI3K-AKT pathway. Here, we further investigated the proteomic changes within the rat cortex and hippocampus following mild TBI (TM), severe TBI (TS), or severe TBI plus MA treatment (TSm) compared to sham operated controls (n=78 in total). We quantified >7,000 unique proteins in total and identified 402 and 801 altered proteins (APs) with high confidence in cortical and hippocampal tissues, respectively. The overall profile of APs observed in TSm rats more closely resembled those seen in TM rather than TS rats. Pathway analysis suggested beneficial roles for acute signaling through IL-6, TGFβ, and IL-1β. Moreover, changes in fibrinogen levels observed in TSm rats suggested a potential role for these proteins in reducing/preventing TBI-induced coagulopathies. These data facilitate further investigations to identify specific pathways and proteins that may serve as key targets for the development of neuroprotective therapies.

2021-03-02 | PXD024317 | Pride

T cell infiltration as a novel therapeutic target in aged traumatic brain injury

Project description:Patients aged 65 years and older account for an increasing proportion of those who suffer from traumatic brain injury (TBI). Aged TBI patients experience increased morbidity and mortality compared to young TBI patients. Our prior data demonstrated that anti-CD49d antibody (aCD49d Ab), an FDA-approved drug that blocks α4 integrin, abrogates infiltration of CD8+ T-cells into the injured brain, improves survival, and attenuates neurocognitive deficits. Yet, the molecular mechanisms underlying the therapeutic effects of aCD49d Ab remained unexplored. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, we found that mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of CD8+ T cell cytotoxicity. Further, aCD49d Ab further produces a neuroprotective Th2 response and restores age-associated CD8+ T cell senescence. Our results demonstrate that targeting infiltrating CD8+ T cells with aCD49d Ab is a promising therapeutic strategy for treating TBI in aged individuals.

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Hippocampus-Cerebellum Axis Specific Transcriptomic Stratification to Discriminate Mild from Moderate TBI

Project description:The variations of psycho- and physiological deficits caused by TBI correlate with the degree of brain injury. However, the objective stratification of TBI is yet elusive. A modified closed-head injury Marmarou model was used based on the release of a 500 gram steel slug on top of the rat skull from a height of 100 cm or 120 cm to induce differential injury models for mild TBI and moderate TBI, respectively. The skull was covered by a helmet to mimic the warfighter’s condition in theater. The hippocampus was at the focal point of injury, and the cerebellum, was susceptible to diffused shock (secondary injury). The HC-CB axis coordinates visuomotor performance, which is known to be vulnerable to TBI. The rats that received moderate TBI showed deficient visuomotor performance by the Barnes maze test for longer time periods than those inflicted with mild TBI. The time resolved and HC-CB specific transcriptomic analysis focused on genes that enabled discrimination of mild from moderate TBI at 14d post injury which is equivalent to nearly 1.5 years of human lifetime. The functional analysis elucidated an active healing mechanism in the HC exposed to mild TBI. In contrast, moderate TBI caused delayed healing and active cell death in the HC. In conclusion, the graded brain injuries differentially implicated the HC-CB axis, despite the use of a helmet to reduce the impact. Time resolved functional dynamics informed the distinct consequences of mild vs. moderate TBI.

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Treatment with antidepressant drugs in a rat model of Traumatic Brain Injury

Project description:Microarray analysis was performed to look at the mRNA and miRNA profiles of several antidepressant drugs in the rat hippocampus after Traumatic Brain Injury to test the hypothesis that antidepressant drugs ameliorate gene and miRNA dysregulation after TBI.

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