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Chronic social isolation stress (SIS) could impair learning and memory-related behaviors. Herein, we investigated the efficacy of Melatonin in treatment of memory despair and also its possible underlying mechanism of action in an animal model of SIS. For this purpose, mice were allocated to two opposing conditions, including social condition (SC) and isolated condition (IC), for five weeks. The study consisted of three groups, including saline-treated SC, saline-treated IC, Melatonin-treated IC (10 mg/kg/day for five successive days). At the end of the isolation period, mice underwent three neurobehavioral tests: passive avoidance (PA), Morris water maze (MWM), and Y maze (YM) tests. Hippocampus samples were obtained and the expressions of BDNF, TrkB, phosphorylated TrkB (pTrkB), CREB, phosphorylated CREB (pCREB), as well as M1 and M2 microglia were assessed. Interpreting the behavioral tests, we found that isolated mice showed lower freezing response in the PA test, lower number of novel arm visits in the YM, and higher escape latency and less time spent in the target quadrant in the MWM, when compared to SC rodents (P values < 0.001). The isolated group had higher M1/M2 relative ratio (P < 0.001), as well as lower concentrations of BDNF mRNA (p < 0.001) and protein (P < 0.001), TrkB protein (P = 0.035), CREB mRNA (P < 0.001) and protein (P = 0.012), pTrkB (P < 0.001), and pCREB (P = 0.035). However, Melatonin relatively reversed the behavioral, cellular, and molecular effects of SIS. Taken together, melatonin therapy could alleviate memory impairment through switching microglial polarization from M1 to M2 phenotype along with altered expression and function in the BDNF/TrkB/CREB signaling pathway. Animals with chronic social isolation stress show significant impairment in various domains of learning and memory. As depicted in the graph, however, this impairment could be reversed by melatonin therapy. One of the major melatonin mechanisms of action appears to be through BDNF/TrkB/CREB signaling pathway, where its administration could restore the reduced levels and function of the pathway components. Beyond that, the graph suggests the prominent effect of melatonin on M1 and M2 microglia polarization as a possible explanation for its impact on the BDNF signaling. In other words, the elevation in the expression level of M2 microglia along with the reduction of M1 microglia results in higher secretion of M2-derived BDNF. This could lead to the activation of intraneuronal cascades, which finally gives rise to the promotion in the level of Neuron-derived BDNF as a neuroprotective factor. [Display omitted] [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by impairments in social and cognitive activities, stereotypical and repetitive behaviors and restricted areas of interest. A remarkable proportion of ASD patients represent immune dysregulation as well as gastrointestinal complications. Hence, a novel concept has recently emerged, addressing the possible intercommunication between the brain, the immune system, the gut and its commensals. Here, we provide an overview of how gut microbes and their metabolites are associated with neurobehavioral features of ASD through various immunologic mechanisms. Moreover, we discuss the potential therapeutic options that could modify these features. • Children with ASD represent high rates of gastrointestinal complications. • Gut microbiota affects the immune system via various signaling pathways. • Gut-brain axis is defined as a bidirectional interaction between gut microbiota and brain. • Inappropriate stimulation of the immune system disrupts brain function through different mechanisms. • Modifying the microbiota alterations via psychobiotics could reverse the ASD-related behaviors. [ABSTRACT FROM AUTHOR]

• There is ongoing effort to discover an efficient approach for management of spinal cord injury (SCI) complications. • Roflumilast is able to alleviate locomotor and sensory complications of SCI. • Roflumilast is a highly selective inhibitor of phosphodiesterase 4 and can enhance the intracellular cAMP level. • Roflumilast decreases the relative ratio of pro-inflammatory (M1) to anti-inflammatory (M2) microglia in the lesion site. • Roflumilast attenuates the secondary damage of SCI through reducing the neuroinflammation. Despite the great search for an effective approach to minimize secondary injury in spinal cord injury (SCI) setting, there have been limited advances. Roflumilast is a selective inhibitor of phosphodiesterase 4 with potent anti-inflammatory properties. Here, we sought to explore Roflumilast efficacy in the improvement of locomotor and sensory deficits of SCI. In an animal setting, 50 male rats were randomly assigned to five groups: an SCI group receiving Placebo, three SCI groups receiving Roflumilast at the doses of 0.25, 0.5, and 1 mg/kg prior to T9 vertebra laminectomy, and a sham-operated group. Locomotor, mechanical, and thermal activities were evaluated for 28 days. At the end of the study, spinal cord samples were taken to assess the relative ratio of microglial subtypes, including M1 and M2, histopathological changes, levels of pro-inflammatory (TNF-α and IL-1β) and anti-inflammatory (IL-10) biomarkers, and cAMP level. Repeated measure analysis revealed significant effect for time-treatment interaction on locomotion [ F (24, 270) = 280.7, p < 0.001], thermal sensitivity [ F (16, 180) = 4.35, p < 0.001], and mechanical sensitivity [ F (16, 180) = 7.96, p < 0.001]. As expected, Roflumilast significantly increased the expression of spinal cAMP. H&E staining exhibited lesser histopathological disruptions in Roflumilast-treated rodents. We also observed a significant reduction in the M1/M2 ratio (p values < 0.001) as well as in pro-inflammatory biomarkers following the administration of Roflumilast to the injured rats. Furthermore, IL-10 level was increased in rodents receiving 1 mg/kg of the reagent. In conclusion, the increased spinal cAMP following Roflumilast therapy might attenuate neuroinflammation via altering microglial activity; therefore, it could be considered as an alternative therapeutic agent for SCI complications. [ABSTRACT FROM AUTHOR]