The preferential effect of Clemastine on F3/Contactin-1/Notch-1 compared to Jagged-1/Notch-1 justifies its remyelinating effect in an experimental model of multiple sclerosis in rats.

Clemastine (CLM) is repurposed to enhance remyelination in multiple sclerosis (MS) patients. CLM blocks histamine and muscarinic receptors as negative regulators to oligodendrocyte differentiation. These receptors are linked to the canonical and non-canonical Notch-1 signaling via specific ligands; Jagged-1 and F3/Contactin-1, respectively. Yet, there are no previous studies showing the influence of CLM on Notch entities. Herein, the study aimed to investigate to which extent CLM aligns to one of the two Notch-1 arms in experimental autoimmune encephalomyelitis (EAE) rat model. Three groups were utilized where first group received vehicles. The second group was injected by spinal cord homogenate mixed with complete Freund's adjuvant on days 0 and 7. In the third group, CLM (5 mg/kg/day; p.o) was administered for 15 days starting from the day of the first immunization. CLM ameliorated EAE-associated motor and gripping impairment in rotarod, open-field, and grip strength arena beside sensory anomalies in hot plate, cold allodynia, and mechanical Randall-Selitto tests. Additionally, CLM alleviated depressive mood observed in tail suspension test. These findings harmonized with histopathological examinations of Luxol-fast blue stain together with enhanced immunostaining of myelin basic protein and oligodendrocyte lineage gene 2 in corpus callosum and spinal cord. Additionally, CLM enhanced oligodendrocyte myelination and maturation by increasing 2',3'-cyclic nucleotide 3'-phosphodiesterase, proteolipid protein, aspartoacylase as well. CLM restored the level of F3/Contactin-1 in the diseased rats over Jagged-1 level; the ligand of the canonical pathway. This was accompanied by elevated gene expression of Deltex-1 and reduced hairy and enhancer-of-split homologs 1 and 5. Additionally, CLM suppressed microglial and astrocyte activation via reducing the expression of ionized calcium-binding adaptor molecule-1 as well as glial fibrillary acidic protein, respectively. These results outlined the remyelinating beneficence of CLM which could be due to augmenting the non-canonical Notch-1 signaling over the canonical one.

Preclinical Evidence for the Role of the Yin/Yang Angiotensin System Components in Autism Spectrum Disorder: A Therapeutic Target of Astaxanthin.

Autism spectrum disorder (ASD) prevalence is emerging with an unclear etiology, hindering effective therapeutic interventions. Recent studies suggest potential renin-angiotensin system (RAS) alterations in different neurological pathologies. However, its implications in ASD are unexplored. This research fulfills the critical gap by investigating dual arms of RAS and their interplay with Notch signaling in ASD, using a valproic acid (VPA) model and assessing astaxanthin's (AST) modulatory impacts. Experimentally, male pups from pregnant rats receiving either saline or VPA on gestation day 12.5 were divided into control and VPA groups, with subsequent AST treatment in a subset (postnatal days 34-58). Behavioral analyses, histopathological investigations, and electron microscopy provided insights into the neurobehavioral and structural changes induced by AST. Molecular investigations of male pups' cortices revealed that AST outweighs the protective RAS elements with the inhibition of the detrimental arm. This established the neuroprotective and anti-inflammatory axes of RAS (ACE2/Ang1-7/MasR) in the ASD context. The results showed that AST's normalization of RAS components and Notch signaling underscore a novel therapeutic avenue in ASD, impacting neuronal integrity and behavioral outcomes. These findings affirm the integral role of RAS in ASD and highlight AST's potential as a promising treatment intervention, inviting further neurological research implications.

Sesquiterpene lactones; Damsin and neoambrosin suppress cytokine-mediated inflammation in complete Freund's adjuvant rat model via shutting Akt/ERK1/2/STAT3 signaling.

ETHNOPHARMACOLOGIAL RELEVANCE: Although Damsissa (Ambrosia maritima) is traditionally used as anti-inflammatory and diuretic, the biological activity and mechanism of action of its major constituents are to be elucidated. AIM: to decipher the anti-arthritic potential of damsin (DMS) and neoambrosin (NMS) and to unfold their molecular signaling in complete Freund's adjuvant (CFA)-induced arthritis model. MATERIALS AND METHODS: the right hind paw was inoculated with CFA (0.1 ml) at day 0 and 7 while treatments were started from the 14th day and continued for 2 weeks. Rats were randomly assigned into 4 groups; normal group (NRML), CFA-induced arthritis group, CFA-induced arthritis treated with DMS and NMS (10 mg/kg/day) as 3rd and 4th group; respectively. RESULTS: Throughout experimental period, treatments ameliorated the increase of paw volume, knee joint diameter and nociception tests as reflected in open field arena. Also, DSM and NMS suppressed phosphorylation of Akt, STAT-3, ERK1/2 which was further mirrored by inactivation of GSK3ß and downregulation of MCP-1 together with CCN1 and NF-kß in hind paw tissue. Concomitantly, inflammation markers; TNF-α, IL-6, -12 were lowered as confirmed microscopically during examination of hind paw tissue. CONCLUSION: DSM and NMS-induced suppression of NF-kß subdues clinical features of RA most probably through repression of Akt/ERK1/2/STAT3 pathway. Therefore, DMS and NMS can serve as safe and effective treatment for rheumatoid arthritis, one of the most disabling chronic, inflammatory and painful autoimmune disease.