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

Abstract

Traumatic brain injury (TBI) has long-term consequences that include chronic traumatic encephalopathy (CTE) and an elevated risk for Alzheimer's 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 ( Alyenbaawi et al., 2021 ; Locskai et al., 2024 ). 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 (IC 50 = 3.168 × 10 −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 (IC 50 = 8.691 × 10 −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.