GSK-239512

Whether histamine H3 receptor antagonists (H3R‐ANTs)/inverse agonists (H3R‐IAs) provides benefit for the treatment of schizophrenia remains unclear. This meta‐analysis was conducted to address the above clinical question.

Cognitive Function Scale's composite score (primary), seven domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, and social cognition) score, University of California San Diego Performance‐Based Skills Assessment score, psychopathology scales score, discontinuation rate, and incidence of individual adverse events were among the study outcomes. The standardized mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CIs) were calculated.

Our meta‐analysis included 11 double‐blind, randomized, placebo‐controlled trials (n = 754). Our study evaluated ABT‐288, betahistine, betahistine+reboxetine, GSK239512, MK‐0249, and pitolisant. Betahistine has an H1‐receptor agonistic reaction and H3‐receptor antagonistic reaction, while other drugs only have an H3‐receptor antagonistic/inverse agonistic reaction. Hence, we conducted a meta‐analysis for all outcomes divided by betahistine or other pooled H3R‐ANTs/H3R‐IAs. The study results show that betahistine outperformed placebo in the improvement of overall cognitive symptoms (SMD [95% CI] = −0.61 [−1.03, −0.18]), speed of processing (−0.44 [−0.87, −0.02]), attention/vigilance (−0.43 [−0.85, −0.01]), working memory (−0.48 [−0.90, −0.06]), verbal learning (−0.62 [−1.04, −0.19]), visual learning (−0.57 [−1.00, −0.15]), and betahistine+reboxetine was superior in the improvement of depressive symptoms (−4.04 [−5.10, −2.97]). Pitolisant outperformed placebo in depressive symptom improvement (−3.24 [−4.22, −2.26]). However, the results were derived from one betahistine, betahistine+reboxetine, or pitolisant study. Other pooled H3R‐ANTs/H3R‐IAs revealed risk of insomnia (RR [95% CI] = 2.18 [1.05, 4.55]). However, no differences were observed in other any outcomes between betahistine or other pooled H3R‐ANTs/H3R‐IAs and placebo.

Some H3R‐ANTs/H3R‐IAs might provide benefit for the treatment of cognitive symptoms and depressive symptoms in individuals afflicted with schizophrenia.

Repeated mild traumatic brain injury (rmTBI) can lead to development of chronic traumatic encephalopathy (CTE), which is characterized by progressive neurodegeneration with presence of white matter damage, gliosis and hyper-phosphorylated tau. While animal models of rmTBI have been documented, few characterize the molecular pathogenesis and expression profiles of relevant injured brain regions. Additionally, while the usage of transgenic tau mice in rmTBI is prevalent, the effects of tau on pathological outcomes has not been well studied. Here we characterized a 42-impact closed-head rmTBI paradigm on 3-4 month old male C57BL/6 (WT) and Tau-overexpressing mice (Tau58.4). This injury paradigm resulted in chronic gliosis, T-cell infiltration, and demyelination of the optic nerve and associated white matter tracts at 1-month post-injury. At 3-months post-injury, Tau58.4 mice showed progressive neuroinflammation and neurodegeneration in multiple brain regions compared to WT mice. Corresponding to histopathology, RNAseq of the optic nerve tract at 1-month post-injury showed significant upregulation of inflammatory pathways and downregulation of myelin synthetic pathways in both genotypes. However, Tau58.4 mice showed additional changes in neurite development, protein processing, and cell stress. Comparisons with published transcriptomes of human Alzheimer's Disease and CTE revealed common signatures including neuroinflammation and downregulation of protein phosphatases. We next investigated the demyelination and T-cell infiltration phenotypes to determine whether these offer potential avenues for therapeutic intervention. Tau58.4 mice were treated with the histamine H3 receptor antagonist GSK239512 for 1-month post-injury to promote remyelination of white matter lesions. This restored myelin gene expression to sham levels but failed to repair the histopathologic lesions. Likewise, injured T-cell-deficient Rag2/Il2rg (R2G2) mice also showed evidence for inflammation and loss of myelin. However, unlike immune-competent mice, R2G2 mice had altered myeloid cell gene expression and fewer demyelinated lesions. Together this data shows that rmTBI leads to chronic white matter inflammatory demyelination and axonal loss exacerbated by human tau overexpression but suggests that immune-suppression and remyelination alone are insufficient to reverse damage.