Liraglutide Improves Cognitive and Neuronal Function in 3-NP Rat Model of Huntington’s Disease

Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by progressive motor, psychiatric, and cognitive abnormalities. The antidiabetic drug liraglutide possesses a neuroprotective potential against several neurodegenerative disorders; however, its role in Huntington’s disease (HD) and the possible mechanisms/trajectories remain elusive, which is the aim of this work. Liraglutide (200 μg/kg, s.c) was administered to rats intoxicated with 3-nitropropionic acid (3-NP) for 4 weeks post HD model induction. Liraglutide abated the 3-NP-induced neurobehavioral deficits (open field and elevated plus maze tests) and histopathological changes. Liraglutide downregulated the striatal mRNA expression of HSP 27, PBR, and GFAP, while it upregulated that of DARPP32. On the molecular level, liraglutide enhanced striatal miR-130a gene expression and TrKB protein expression and its ligand BDNF, while it reduced the striatal protein content and mRNA expression of the death receptors sortilin and p75NTR, respectively. It enhanced the neuroprotective molecules cAMP, p-PI3K, p-Akt, and p-CREB, besides modulating the p-GSK-3β/p-β-catenin axis. Liraglutide enhanced the antioxidant transcription factor Nrf2, abrogated TBARS, upregulated both Bcl2 and Bcl-XL, and downregulated Bax along with decreasing caspase-3 activity. Therefore, liraglutide exerts a neurotherapeutic effect on 3-NP-treated rats that is, besides the upturn of behavioral and structural findings, it at least partially, increased miR-130a and modulated PI3K/Akt/CREB/BDNF/TrKB, sortilin, and p75NTR, and Akt/GSK-3β/p-β-catenin trajectories besides its capacity to decrease apoptosis and oxidative stress, as well as its neurotrophic activity.

Developmental exposure to non-dioxin-like polychlorinated biphenyls promotes sensory deficits and disrupts dopaminergic and GABAergic signaling in zebrafish

The most abundant polychlorinated biphenyl (PCB) congeners found in the environment and in humans are neurotoxic. This is of particular concern for early life stages because the exposure of the more vulnerable developing nervous system to neurotoxic chemicals can result in neurobehavioral disorders. In this study, we uncover currently unknown links between PCB target mechanisms and neurobehavioral deficits using zebrafish as a vertebrate model. We investigated the effects of the abundant non-dioxin-like (NDL) congener PCB153 on neuronal morphology and synaptic transmission linked to the proper execution of a sensorimotor response. Zebrafish that were exposed during development to concentrations similar to those found in human cord blood and PCB contaminated sites showed a delay in startle response. Morphological and biochemical data demonstrate that even though PCB153-induced swelling of afferent sensory neurons, the disruption of dopaminergic and GABAergic signaling appears to contribute to PCB-induced motor deficits. A similar delay was observed for other NDL congeners but not for the potent dioxin-like congener PCB126. The effects on important and broadly conserved signaling mechanisms in vertebrates suggest that NDL PCBs may contribute to neurodevelopmental abnormalities in humans and increased selection pressures in vertebrate wildlife.

Association of Pericyte Loss With Microthrombosis After Subarachnoid Hemorrhage in ApoE-Deficient Mice

Background: The occurrence of microthrombosis contributes to not only delayed cerebral ischemia (DCI), but also early brain injury (EBI) after SAH. However, the underlying mechanism is not completely investigated. In the current study, we explored the underlying mechanism of microthrombosis in EBI stage after SAH in ApoE-deficient mice.Methods: Experimental SAH was established by endovascular perforation in apolipoprotein E (ApoE)-deficient mice and wild type (WT) mice. Neurobehavioral, molecular biological and histopathological methods were used to assess the relationship between pericytes loss, neurobehavioral performance, and microthrombosis.Results: We found that the number of microthrombi was significantly increased and peaked 48 h after SAH in WT mice. The increased microthrombosis was related to the decreased effective microcirculation perfusion area and EBI severity. ApoE-deficient mice showed more extensive microthrombosis than that of WT mice 48 h after SAH, which was thereby associated with greater neurobehavioral deficits. Immunohistochemical staining showed that microthrombi were predominantly located in microvessels where pericytes coverage was absent. Mechanistically, ApoE deficiency caused more extensive CypA-NF-κB-MMP-9 pathway activation than that observed in WT mice, which thereby led to more degradation of N-cadherin, and subsequently more pericytes loss. Thereafter, the major adhesion molecule that promoting microthrombi formation in microvessels, P-selectin, was considerably increased in WT mice and increased to a greater extent in the ApoE-deficient mice.Conclusion: Taken together, these data suggest that pericytes loss is associated with EBI after SAH through promoting microthrombosis. Therapies that target ApoE to reduce microthrombosis may be a promising strategy for SAH treatment.

Temporal dissection of Rai1 function reveals brain-derived neurotrophic factor as a potential therapeutic target for Smith-Magenis syndrome

Haploinsufficiency of RAI1 is responsible for Smith-Magenis Syndrome (SMS), a childhood neurodevelopmental disorder associated with hyperphagia, obesity, and autistic features. We previously showed that constitutive inactivation of one or both copies of Rai1 in the germline or developing brain induces SMS-like neurobehavioral deficits and obesity in mice. By contrast, the postnatal function of Rai1 is unclear. Here, we globally deleted one or both copies of Rai1 during two postnatal developmental windows by generating an inducible Rai1 knockout mouse model. We found that delayed Rai1 deletion at 3 or 8 weeks of age had no effect on neurobehavioral functions but resulted in adult-onset obesity and decreased expression of brain-derived neurotrophic factor (Bdnf) in the hypothalamus. Remarkably, genetic overexpression of human Bdnf in Rai1 heterozygous mice reversed SMS-like obesity, hyperphagia, metabolic syndrome-like features, and hyposociability. Increasing Bdnf signaling in the paraventricular nucleus of the hypothalamus (PVH) or the ventromedial nucleus of the hypothalamus (VMH) was sufficient to mediate the anti-obesity effect. Our work identifies the function of Rai1 in different temporal windows after birth and provides in vivo evidence that increasing Bdnf signaling is therapeutically effective in a preclinical mouse model of SMS.