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Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury.

ABSTRACT: Traumatic brain injury (TBI) causes cortical dysfunction and can lead to post-traumatic epilepsy. Multiple studies demonstrate that GABAergic inhibitory network function is compromised following TBI, which may contribute to hyperexcitability and motor, behavioral, and cognitive deficits. Preserving the function of GABAergic interneurons, therefore, is a rational therapeutic strategy to preserve cortical function after TBI and prevent long-term clinical complications. Here, we explored an approach based on the ketogenic diet, a neuroprotective and anticonvulsant dietary therapy which results in reduced glycolysis and increased ketosis. Utilizing a pharmacologic inhibitor of glycolysis (2-deoxyglucose, or 2-DG), we found that acute in vitro application of 2-DG decreased the excitability of excitatory neurons, but not inhibitory interneurons, in cortical slices from naïve mice. Employing the controlled cortical impact (CCI) model of TBI in mice, we found that in vitro 2-DG treatment rapidly attenuated epileptiform activity seen in acute cortical slices 3 to 5 weeks after TBI. One week of in vivo 2-DG treatment immediately after TBI prevented the development of epileptiform activity, restored excitatory and inhibitory synaptic activity, and attenuated the loss of parvalbumin-expressing inhibitory interneurons. In summary, 2-DG may have therapeutic potential to restore network function following TBI.

SUBMITTER: Koenig JB

PROVIDER: S-EPMC6629107 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury.

Koenig Jenny B JB Cantu David D Low Cho C Sommer Mary M Noubary Farzad F Croker Danielle D Whalen Michael M Kong Dong D Dulla Chris G CG

JCI insight 20190430

Traumatic brain injury (TBI) causes cortical dysfunction and can lead to post-traumatic epilepsy. Multiple studies demonstrate that GABAergic inhibitory network function is compromised following TBI, which may contribute to hyperexcitability and motor, behavioral, and cognitive deficits. Preserving the function of GABAergic interneurons, therefore, is a rational therapeutic strategy to preserve cortical function after TBI and prevent long-term clinical complications. Here, we explored an approac ...[more]

PMID: 31038473

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Project description:We investigated the contribution of excitatory transient receptor potential canonical (TRPC) cation channels to posttraumatic hyperexcitability in the brain 7 days following controlled cortical impact model of traumatic brain injury (TBI) to the parietal cortex in male adult mice. We investigated if TRPC1/TRPC4/TRPC5 channel expression is upregulated in excitatory neurons after TBI in contribution to epileptogenic hyperexcitability in key hippocampal and cortical circuits that have substantial cholinergic innervation. This was tested by measuring TRPC1/TRPC4/TRPC5 protein and messenger RNA (mRNA) expression, assays of cholinergic function, neuronal Ca2+ imaging in brain slices, and seizure susceptibility after TBI. We found region-specific increases in expression of TRPC1, TRPC4, and TRPC5 subunits in the hippocampus and cortex following TBI. The dentate gyrus, CA3 region, and cortex all exhibited robust upregulation of TRPC4 mRNA and protein. TBI increased cFos activity in dentate gyrus granule cells (DGGCs) and layer 5 pyramidal neurons both at the time of TBI and 7 days post-TBI. DGGCs displayed greater magnitude and duration of acetylcholine-induced rises in intracellular Ca2+ in brain slices from mice subjected to TBI. The TBI mice also exhibited greater seizure susceptibility in response to pentylenetetrazol-induced kindling. Blockade of TRPC4/TRPC5 channels with M084 reduced neuronal hyperexcitation and impeded epileptogenic progression of kindling. We observed that the time-dependent upregulation of TRPC4/TRPC5-containing channels alters cholinergic responses and activity of principal neurons acting to increase proexcitatory sensitivity. The underlying mechanism includes acutely decreased acetylcholinesterase function, resulting in greater G q / 11-coupled muscarinic receptor activation of TRPC channels. Overall, our evidence suggests that TBI-induced plasticity of TRPC channels strongly contributes to overt hyperexcitability and primes the hippocampus and cortex for seizures.

Project description:The main objective of this study was to determine the cellular and molecular effects of doxycycline on the blood-brain barrier (BBB) and protection against secondary injuries following traumatic brain injury (TBI). Microvascular hyperpermeability and cerebral edema resulting from BBB dysfunction after TBI leads to elevation of intracranial pressure, secondary brain ischemia, herniation, and brain death. There are currently no effective therapies to modulate the underlying pathophysiology responsible for TBI-induced BBB dysfunction and hyperpermeability. The loss of BBB integrity by the proteolytic enzyme matrix metalloproteinase-9 (MMP-9) is critical to TBI-induced BBB hyperpermeability, and doxycycline possesses anti-MMP-9 effect. In this study, the effect of doxycycline on BBB hyperpermeability was studied utilizing molecular modeling (using Glide) in silico, cell culture-based models in vitro, and a mouse model of TBI in vivo. Brain microvascular endothelial cell assays of tight junction protein immunofluorescence and barrier permeability were performed. Adult C57BL/6 mice were subjected to sham versus TBI with or without doxycycline treatment and immediate intravital microscopic analysis for evaluating BBB integrity. Postmortem mouse brain tissue was collected to measure MMP-9 enzyme activity. It was found that doxycycline binding to the MMP-9 active sites have binding affinity of -7.07 kcal/mol. Doxycycline treated cell monolayers were protected from microvascular hyperpermeability and retained tight junction integrity (p < 0.05). Doxycycline treatment decreased BBB hyperpermeability following TBI in mice by 25% (p < 0.05). MMP-9 enzyme activity in brain tissue decreased with doxycycline treatment following TBI (p < 0.05). Doxycycline preserves BBB tight junction integrity following TBI via inhibiting MMP-9 activity. When established in human subjects, doxycycline, may provide readily accessible medical treatment after TBI to attenuate secondary injury.

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Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury.

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Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury.

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