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Background/objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social interaction difficulties, repetitive behaviors, and immune dysregulation with elevated pro-inflammatory markers. Autophagic deficiency also contributes to social behavior deficits in ASD. Histamine H3 receptor (H3R) antagonism is a potential treatment strategy for brain disorders with features overlapping ASD, such as schizophrenia and Alzheimer's disease., Methods: This study investigated the effects of sub-chronic systemic treatment with the H3R antagonist E159 on social deficits, repetitive behaviors, neuroinflammation, and autophagic disruption in male BTBR mice., Results: E159 (2.5, 5, and 10 mg/kg, i.p.) improved stereotypic repetitive behavior by reducing self-grooming time and enhancing spontaneous alternation in addition to attenuating social deficits. It also decreased pro-inflammatory cytokines in the cerebellum and hippocampus of treated BTBR mice. In BTBR mice, reduced expression of autophagy-related proteins LC3A/B and Beclin 1 was observed, which was elevated following treatment with E159, attenuating the disruption in autophagy. The co-administration with the H3R agonist MHA (10 mg/kg, i.p.) reversed these effects, highlighting the role of histaminergic neurotransmission in observed behavioral improvements., Conclusions: These preliminary findings suggest the therapeutic potential of H3R antagonists in targeting neuroinflammation and autophagic disruption to improve ASD-like behaviors.

Histamine performs dual roles as an immune regulator and a neurotransmitter in the mammalian brain. The histaminergic system plays a vital role in the regulation of wakefulness, cognition, neuroinflammation, and neurogenesis that are substantially disrupted in various neurodegenerative and neurodevelopmental disorders. Histamine H3 receptor (H3R) antagonists and inverse agonists potentiate the endogenous release of brain histamine and have been shown to enhance cognitive abilities in animal models of several brain disorders. Microglial activation and subsequent neuroinflammation are implicated in impacting embryonic and adult neurogenesis, contributing to the development of Alzheimer's disease (AD), Parkinson's disease (PD), and autism spectrum disorder (ASD). Acknowledging the importance of microglia in both neuroinflammation and neurodevelopment, as well as their regulation by histamine, offers an intriguing therapeutic target for these disorders. The inhibition of brain H3Rs has been found to facilitate a shift from a proinflammatory M1 state to an anti-inflammatory M2 state, leading to a reduction in the activity of microglial cells. Also, pharmacological studies have demonstrated that H3R antagonists showed positive effects by reducing the proinflammatory biomarkers, suggesting their potential role in simultaneously modulating crucial brain neurotransmissions and signaling cascades such as the PI3K/AKT/GSK-3β pathway. In this review, we highlight the potential therapeutic role of the H3R antagonists in addressing the pathology and cognitive decline in brain disorders, e.g., AD, PD, and ASD, with an inflammatory component.

The coordination chemistry of scorpionate ligands based on borates containing the 7-azaindole heterocycle is relatively unexplored. Thus, there is a requirement to further understand their coordination chemistry. This article outlines the synthesis and characterization of a family of complexes containing anionic flexible scorpionate ligands of the type [(R)(bis-7-azaindolyl)borohydride] - ([ R Bai ] - ), where R = Me, Ph or naphthyl. The three ligands were coordinated to a series of copper(I) complexes containing a phosphine co-ligand to form the complexes, [Cu( Me Bai )(PPh 3 )] ( 1 ), [Cu( Ph Bai )(PPh 3 )] ( 2 ), [Cu( Naphth Bai )(PPh 3 )] ( 3 ), [Cu( Me Bai )(PCy 3 )] ( 4 ), [Cu( Ph Bai )(PCy 3 )] ( 5 ) and [Cu( Naphth Bai )(PCy 3 )] ( 6 ). Additional copper(II) complexes, namely, [Cu( Me Bai ) 2 ] ( 7 ) and [Cu( Ph Bai ) 2 ] ( 8 ), were obtained during attempts to obtain single crystals from complexes 4 and 2 , respectively. Complexes 7 and 8 were also prepared independently from CuCl 2 and two equivalents of the corresponding Li[ R Bai ] salt alongside an additional complex, namely, [Cu( Naphth Bai ) 2 ] ( 9 ). The copper(I) and copper(II) complexes were characterized using spectroscopic and analytical methods. Furthermore, a crystal structure was obtained for eight of the nine complexes. In all cases, the boron-based ligand was found to bind to the metal centers via a κ 3 - N , N , H coordination mode.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication along with repetitive stereotypic behaviors. Currently, there are no specific biomarkers for diagnostic screening or treatments available for autistic patients. Numerous genetic disorders are associated with high prevalence of ASD, including tuberous sclerosis complex, phosphatase and tensin homolog, and fragile X syndrome. Preclinical investigations in animal models of these diseases have revealed irregularities in the PI3K/Akt/mTOR signaling pathway as well as ASD-related behavioral defects. Reversal of the downstream molecular irregularities, associated with mTOR hyperactivation, improved the behavioral deficits observed in the preclinical investigations. Plant bioactive molecules have shown beneficial pre-clinical evidence in ASD treatment by modulating the PI3K/Akt/mTOR pathway. In this review, we summarize the involvement of the PI3K/Akt/mTOR pathway as well as the genetic alterations of the pathway components and its critical impact on the development of the autism spectrum disorder. Mutations in negative regulators of mTORC1, such as TSC1, TSC2, and PTEN, result in ASD-like phenotypes through the disruption of the mTORC1-mediated signaling. We further discuss the various naturally occurring phytoconstituents that have been identified to be bioactive and modulate the pathway to prevent its disruption and contribute to beneficial therapeutic effects in ASD.

Dysregulation in brain neurotransmitters underlies several neuropsychiatric disorders, e.g., autism spectrum disorder (ASD). Also, abnormalities in the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway pave the way for neuroinflammation, neurodegeneration, and altered learning phenotype in ASD. Therefore, the effects of chronic systemic administration of the multiple-targeting antagonist ST-713 at the histamine H3 receptor (H3R) and dopamine D2/D3 receptors (D2/D3R) on repetitive self-grooming, aggressive behaviors, and abnormalities in the MAPK pathway in BTBR T + Itpr3tf/J (BTBR) mice were assessed. The results showed that ST-713 (2.5, 5, and 10 mg/kg, i.p.) mitigated repetitive self-grooming and aggression in BTBR mice (all p < 0.05), and the ameliorative effects of the most promising dose of ST-713 (5 mg/kg, i.p.) on behaviors were completely abrogated by co-administration of the H3R agonist (R)-α-methylhistamine or the anticholinergic drug scopolamine. Moreover, the elevated levels of several MAPK pathway proteins and induced proinflammatory markers such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and IL-6 were significantly suppressed following chronic administration of ST-713 (5 mg/kg, i.p.) (all p < 0.01). Furthermore, ST-713 significantly increased the levels of histamine and dopamine in hippocampal tissue of treated BTBR mice (all p < 0.01). The current observations signify the potential role of such multiple-targeting compounds, e.g., ST-713, in multifactorial neurodevelopmental disorders such as ASD.

Dimethyl fumarate (DMF) is a small molecule that has been shown to assert potent in vivo immunoregulatory and anti-inflammatory therapeutic actions. The drug has been approved and is currently in use for treating multiple sclerosis and psoriasis in the USA and Europe. Since inflammatory reactions have been significantly implicated in the etiology and progression of diverse disease states, the pharmacological actions of DMF are presently being explored and generalized to other diseases where inflammation needs to be suppressed and immunoregulation is desirable, either as a monotherapeutic agent or as an adjuvant. In this review, we focus on DMF, and present an overview of its mechanism of action while briefly discussing its pharmacokinetic profile. We further discuss in detail its pharmacological uses and highlight its potential applications in the treatment of cardiovascular diseases. DMF, with its unique combination of anti-inflammatory and vasculoprotective effects, has the potential to be repurposed as a therapeutic agent in patients with atherosclerotic cardiovascular disease. The clinical studies mentioned in this review with respect to the beneficial effects of DMF in atherosclerosis involve observations in patients with multiple sclerosis and psoriasis in small cohorts and for short durations. The findings of these studies need to be assessed in larger prospective clinical trials, ideally with a double-blind randomized study design, investigating the effects on cardiovascular endpoints as well as morbidity and mortality. The long-term impact of DMF therapy on cardiovascular diseases also needs to be confirmed.

The aim of this study was to assess the effect of exercise intensity on the thermal sensory function of active and inactive limbs. In a randomised and counterbalanced manner, 13 healthy young male participants (25 ± 6 years, 1.8 ± 0.1 m, 77 ± 6 kg) conducted: (1) 30-min low-intensity (50% heart rate maximum, HRmax; LOW) and (2) 30-min high-intensity (80% HRmax; HIGH) cycling exercises, and (3) 30 min of seated rest (CONTROL). Before, immediately after, and 1 h after, each intervention, thermal sensory functions of the non-dominant dorsal forearm and posterior calf were examined by increasing local skin temperature (1 °C/s) to assess perceptual heat sensitivity and pain thresholds. Relative to pre-exercise, forearm heat sensitivity thresholds were increased immediately and 1 hr after HIGH, but there were no changes after LOW exercise or during CONTROL (main effect of trial; p = 0.017). Relative to pre-exercise, calf heat sensitivity thresholds were not changed after LOW or HIGH exercise or during CONTROL (main effect of trial; p = 0.629). There were no changes in calf (main effect of trial; p = 0.528) or forearm (main effect of trial; p = 0.088) heat pain thresholds after exercise in either LOW or HIGH or CONTROL. These results suggest that cutaneous thermal sensitivity function of an inactive limb is only reduced after higher intensity exercise but is not changed in a previously active limb after exercise. Exercise does not affect heat pain sensitivity in either active or inactive limbs.

The purpose of the study was to describe conditions and dynamics in the lives of high-risk, low-income, Southern United States prenatal-interconceptional women ( n = 37) in a home visiting program that promoted maternal health literacy progression. In the Life Course Health Development (LCHD) Model, conditions were risk and protective factors that impacted health. Dynamics drove the complex, epigenetic relationships between risk and protective factors. Maternal health literacy promotion helped participants address conditions and dynamics to create positive life changes. This research was a retrospective, mixed methods study of women's service records documenting care from prenatal admission to 24 months post-delivery. The Life Skills Progression Instrument (LSP) was scored to measure maternal health literacy progression. Ethnographic content analysis of visit notes triangulated with quantitative data enabled specificity of critical data elements. Subsequently, a complementary focus group was conducted with the Registered Nurse Case Managers (RNCM). Severe social conditions included devastating poverty, low educational achievement, transient housing, unstable relationships, incarceration, lack of continuous health insurance, and shortage of health care providers. Dynamics included severe psycho-social stressors, domestic violence, lack of employment, low income, low self-esteem and self-expectations, and social/family restraints upon women's intended positive changes. An important protective factor was the consistent, stable, evidence-informed relationship with the RNCM. Findings from the focus group discussion supported content analysis results.