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. 2022 Feb 14:16:832478.
doi: 10.3389/fnins.2022.832478. eCollection 2022.

Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model

Dmitry Frank  1 , Benjamin F Gruenbaum  2 , Ilan Shelef  3 , Vladislav Zvenigorodsky  3 , Olena Severynovska  4 , Ron Gal  1 , Michael Dubilet  1 , Alexander Zlotnik  1 , Ora Kofman  5 , Matthew Boyko  1
Affiliations

Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model

Dmitry Frank et al. Front Neurosci. .

Abstract

Depression is a common and serious complication following traumatic brain injury (TBI). Both depression and TBI have independently been associated with pathologically elevated extracellular brain glutamate levels. In the setting of TBI, blood glutamate scavenging with pyruvate has been widely shown as an effective method to provide neuroprotection by reducing blood glutamate and subsequent brain glutamate levels. Here we evaluate pyruvate as a novel approach in the treatment and prevention of post-TBI depression-like behavior in a rat model. Rats were divided into five groups: (1) sham-operated control with pyruvate, (2) sham-operated control with placebo, (3) post-TBI with placebo, (4) post-TBI given preventative pyruvate, and (5) post-TBI treated with pyruvate. These groups had an equal number of females and males. Rats were assessed for depressive-like behavior, neurological status, and glutamate levels in the blood and brain. Post-TBI neurological deficits with concurrent elevations in glutamate levels were demonstrated, with peak glutamate levels 24 h after TBI. Following TBI, the administration of either prophylactic or therapeutic pyruvate led to reduced glutamate levels, improved neurologic recovery, and improved depressive-like behavior. Glutamate scavenging with pyruvate may be an effective prophylactic and therapeutic option for post-TBI depression by reducing associated elevations in brain glutamate levels.

Keywords: depression; glutamate scavenging; neuroprotection; pyruvate; traumatic brain injury.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
A timeline of the protocol for preventative (axis A) and treatment (axis B) approach. CSF, Cerebrospinal fluid; NSS, Neurological severity score; PLAC, Placebo; PYR, Pyruvate; TBI, Traumatic brain injury.
FIGURE 2
FIGURE 2
Neurological outcome (A,B) and MRI-determined lesion volume (C,D) and brain edema (E,F). Compared to sham-operated controls, the NSS at 24 h was significantly greater in male [p < 0.01 (A)] and female [p < 0.01 (B)] rats after TBI. The data are measured as a count and expressed as median and 25–75 percentile range. Compared to sham-operated rats, the lesion volume at 24 h was significantly greater in the male [p < 0.01 (C)] and female [p < 0.01 (D)] TBI groups. The data is expressed as a mean percentage of the contralateral hemisphere ± SD. Compared to sham-operated rats, the brain edema at 24 h was significantly greater in the male [p < 0.01, (E)] and female [p < 0.01 (F)] TBI groups. The data are expressed as a mean percentage of the contralateral hemisphere ± SD. TBI: Traumatic brain injury.
FIGURE 3
FIGURE 3
Brain (A,B) and blood (C,D) glutamate concentrations. Compared to sham-operated rats, the concentrations of CSF glutamate at 24 h was significantly greater in the male [p < 0.01, (A)] and female [p < 0.01 (B)] TBI groups. The data are measured in μM/L and expressed as mean ± SD. Blood glutamate levels were decreased in male [p < 0.05 (C)] and female [p < 0.05 (D)] groups that received preventative or therapeutic pyruvate. The data are measured in μM/L presented as a percentage from baseline and expressed as mean ± SEM. CSF, Cerebrospinal fluid; PLAC, Placebo; PYR, Pyruvate; TBI, Traumatic brain injury.
FIGURE 4
FIGURE 4
Sucrose preference test. There was a decrease in sucrose preference at 1 and 3 months following TBI for male (A) and female (B) rats given placebo compared to sham-operated controls (p < 0.01). For male (C) and female (D) rats at day 30, there was a significant decrease in sucrose preference in post-TBI rats given placebo (p < 0.01) and post-TBI rats treated with pyruvate (p < 0.01) compared to sham-operated controls given placebo. For male (E) and female (F) rats at day 90, there was a significant decrease in sucrose preference in post-TBI rats given placebo (p < 0.01) compared to sham-operated controls given placebo. The data are measured as a percentage and presented as mean ± SEM. PLAC, Placebo; PYR, Pyruvate; TBI, Traumatic brain injury.
FIGURE 5
FIGURE 5
Open-field test. There was an increase in the total traveled distance at 1 and 3 months following TBI for male (A) and female (B) rats given placebo compared to sham-operated controls (p < 0.05). For male (C) and female (D) rats at day 30, there was a significant increase in total distance traveled in post-TBI rats given placebo (p < 0.01) and post-TBI rats treated with pyruvate (p < 0.01) compared to sham-operated controls given placebo. For male (E) and female (F) rats at day 90, there was a significant increase in total distance traveled in post-TBI rats given placebo (p < 0.01) compared to sham-operated controls given placebo. The data are measured as cm/5 min and presented as mean ± SEM. PLAC, Placebo; PYR, Pyruvate; TBI, Traumatic brain injury.
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References

    1. Abekawa T., Ito K., Koyama T. (2007). Different effects of a single and repeated administration of clozapine on phencyclidine-induced hyperlocomotion and glutamate releases in the rat medial prefrontal cortex at short-and long-term withdrawal from this antipsychotic. Naunyn Schmiedebergs Arch. Pharmacol. 375 261–271. 10.1007/s00210-007-0154-x - DOI - PubMed
    1. Aitta-Aho T., Maksimovic M., Dahl K., Sprengel R., Korpi E. R. (2019). Attenuation of novelty-induced hyperactivity of Gria1-/-mice by cannabidiol and hippocampal inhibitory chemogenetics. Front. Pharmacol. 10:309. 10.3389/fphar.2019.00309 - DOI - PMC - PubMed
    1. American Psychiatric Pub (2013). Diagnostic and Statistical Manual of Mental Disorders (DSM-5§). Washington, DC: American Psychiatric Pub.
    1. Andersen G., Vestergaard K., Lauritzen L. (1994). Effective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke 25 1099–1104. 10.1161/01.str.25.6.1099 - DOI - PubMed
    1. Angst J., Dobler-Mikola A. (1985). The zurich study. V. Anxiety and phobia in young adults. Eur. Arch. Psychiatry Neurol. Sci. 235 171–178. 10.1007/BF00380989 - DOI - PubMed

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