Diazoxide/dibenozylmethane treatment mitigates spatial memory deficits and pathology and upregulates protective genes in an Alzheimer’s transgenic rat model

Abstract

AbstractINTRODUCTIONAlzheimer’s disease (AD) is a multifactorial disease for which therapeutic efficacy should benefit from a multi-target approach. Thus, we evaluated a combined chronic treatment with diazoxide (DZ) and dibenzoylmethane (DIB). DZ is a potassium channel activator. DIB counteract eIF2α-P-driven stress responses. The individual therapeutic benefits of each drug on attenuating neurodegeneration and apoptosis were previously examined, but not as a combined treatment.METHODSWe evaluated the efficacy of chronic DZ/DIB treatment on TgF344-AD rats (Tg-AD) at 4- and 11-months of age and wild-type littermates. Spatial working memory was assessed with the radial 8-arm maze, and AD pathology by immunohistochemistry. We used RNA sequencing for transcriptome analysis.RESULTSDZ/DIB-treatment mitigated the spatial memory deficits as well as the buildup of hippocampal Aβ plaques and tau PHF exhibited by 11-month Tg-AD rats. The DZ/DIB-treatment had no effect on wild-type littermates. We did not detect AD-related deficits in untreated 4-month Tg-AD rats, but DZ/DIB-treatment altered their transcriptome. DZ/DIB-treatment of 4-month Tg-AD rats upregulated several genes normally downregulated in AD and/or aging. Expression of two potential early biomarkers for AD,EGR2(early growth response 2) andHISIT1H2AA(histone H2AA), were also altered by the DZ/DIB treatment in 4-month Tg-AD rats. The treatment reduced levels of eIF2α, a protein involved in abnormal translational repression and a contributing factor to neuronal loss.DISCUSSIONThis preclinical study represents the first report on the combined DZ/DIB-treatment. Besides the benefits of this treatment on spatial memory and AD pathology, we identified two potential early AD biomarkers. Furthermore, the DZ/DIB-treatment prevented downregulation of genes associated with AD and/or aging. Overall, our results strongly support that the combination DZ/DIB-treatment mitigates AD pathology. Evaluations across multiple AD-related models are warranted to further corroborate that the DZ/DIB combination is a candidate treatment for AD.HighlightsDZ/DIB treatment improves cognitive deficits and AD pathology in TgF344-AD ratsEGR2andHISIT1H2AAgenes are potential early AD biomarkers in TgF344-AD ratsDZ/DIB treatment of 4-month TgF344-AD rats blocks downregulation of AD/aging genesRESEARCH IN CONTEXT1. Systematic Review: We reviewed the literature using traditional sources (e.g., PubMed) to assess the status of DZ and DIB treatment individually in preclinical studies in animal models. To our knowledge there is no data with this chronic combined treatment.2. Interpretation: Treatment takes advantage of a polypharmacological approach to AD therapeutics, considering the multifactorial nature of AD. DZ and DIB individually have been successful in mitigating hippocampal AD pathology but their combined effects were unknown, particularly in a rodent model that shows a more complete disease progression that incorporates aging as a risk factor. The effects of the treatment go beyond previous data in individual DZ and DIB treatment, supporting the need for combination drug treatments to treat a multifactorial disorder.3. Future Directions: Investigate the potential of DZ/DIB treatment to stop the progression or ameliorate AD pathology when administered at a later age, when pathology is first detected.Graphical Abstract