Ghassemi, S. | bioRxiv Science

bioRxiv2026

Traumatic Brain Injury induces persistent behavioural deficits that are rescued by the antiepileptic drug Levetiracetam

Traumatic Brain Injury (TBI) produces acute challenges including seizures and neuroinflammation, and these then exacerbate lifelong difficulties including epilepsy, dementias, and anxiety. Applying antiepileptic drugs (AED) to manage acute seizures after TBI has promise to slow these progressive deficits. Levetiracetam (LEV) is an AED that mitigates seizures and neuroinflammation in various contexts. Here, we explore the utility of the larval zebrafish TBI model by documenting long term behavioural deficits (if any) induced by larval neurotrauma and whether they can be mitigated by LEV. We induced a mild blast TBI in three days-post-fertilization larvae, administered LEV (3 x 10-2 mM) for two days, and assessed behaviour in adults (9 +/- 1 or 22 +/- 1 months later). In open field tests, adult zebrafish that experienced TBI as larvae exhibited increased anxiety-like behaviour compared to sham-treated larvae, but this resolved by later adulthood. LEV treatment immediately following larval TBI did not significantly alter these outcomes. Novel object approach tests revealed sustained deficits in exploratory behaviour: adults that experienced larval TBI spent significantly less time investigating a novel object compared to sham controls throughout adulthood; this suggests long-term alterations in fear-related cognitive processing or threat evaluation. LEV treatment increased time spent near the novel object in early adulthood, but not later adulthood, suggesting a time-dependent efficacy of early pharmacological intervention. In sum, the larval zebrafish TBI model is suitable for investigating the progression and treatment of behavioural deficits. LEV showed only limited efficacy, but adjusted AED regimens have potential to mitigate long-term behavioural outcomes of TBI.

neuroscience↗

bioRxiv2026

JNJ-42153605, a mGluR2 PAM, potentiates Levetiracetam treatments of TBI to mitigate subsequent tau aggregation in a larval zebrafish model

Traumatic brain injury (TBI) has long-term consequences that include chronic traumatic encephalopathy (CTE) and an elevated risk for Alzheimer Disease (AD). These dementias ultimately manifest as tauopathies but may begin with acute neuronal dysfunction including post-traumatic seizures. Provocative evidence suggests that these prodromal seizures are a viable target to mitigate the later onset of dementias, and anti-epileptic drugs (AED) that increase the threshold of action potentials have indeed been shown to mitigate later tauopathies[1, 2]. Here, we test whether AEDs and other compounds that modulate synaptic transmission, applied immediately after TBI, can also act as prophylactics that acutely block subsequent CTE-like tau aggregation and neurodegeneration in a larval zebrafish model expressing a Tau-GFP fusion protein in the CNS. Levetiracetam (LEV) is an AED that modulates synaptic vesicle release. Application of LEV immediately following TBI abrogated TBI-induced tau aggregation (IC50 = 3.168 x10-3 mM) and cell death in the larval zebrafish TBI model. We next considered a polypharmacy approach involving metabotropic glutamate receptor 2 (mGluR2), because mGluR2 positively allosteric modulators (PAMs) such as JNJ-42153605 have previously been able to improve LEV's action in reducing some recalcitrant forms of seizure in a mouse model. We found that JNJ-42153605 was itself effective at blocking TBI-induced tau aggregation (IC50 = 8.691 x10-5 mM). Moreover, a subeffective dose of JNJ-42153605 (10-5 mM) was able to substantially improve the efficacy of LEV (~16-fold) in its prophylactic actions. Thus, LEV and JNJ-42153605 applied briefly after TBI offer a potent polypharmacy approach, at least in our preclinical animal model, to tackle the later tau aggregation and neurodegeneration that follows from TBI neurotrauma. These results warrant further investigation, including testing in mammalian TBI models with longer disease course and more conventional markers of tau pathology.

neuroscience↗