Neuroprotection in non-transgenic and transgenic mouse models of Alzheimer's disease by positive modulation of σ1 receptors.

The sigma-1 (σ1) receptor is an endoplasmic reticulum (ER) chaperone protein, enriched in mitochondria-associated membranes. Its activation triggers physiological responses to ER stress and modulate Ca2+ mobilization in mitochondria. Small σ1 agonist molecules activate the protein and act behaviorally as antidepressant, anti-amnesic and neuroprotective agents. Recently, several chemically unrelated molecules were shown to be σ1 receptor positive modulators (PMs), with some of them a clear demonstration of their allostericity. We here examined whether a σ1 PM also shows neuroprotective potentials in pharmacological and genetic models of Alzheimer's disease (AD). For this aim, we describe (±)-2-(3-chlorophenyl)-3,3,5,5-tetramethyl-2-oxo-[1,4,2]-oxazaphosphinane (OZP002) as a novel σ1 PM. OZP002 does not bind σ1 sites but induces σ1 effects in vivo and boosts σ1 agonist activity. OZP002 was antidepressant in the forced swim test and its effect was blocked by the σ1 antagonist NE-100 or in σ1 receptor knockout mice. It potentiated the antidepressant effect of the σ1 agonist igmesine. In mice tested for Y-maze alternation or passive avoidance, OZP002 prevented scopolamine-induced learning deficits, in a NE-100 sensitive manner. Pre-administered IP before an ICV injection of amyloid Aß25-35 peptide, a pharmacological model of Alzheimer's disease, OZP002 prevented the learning deficits induced by the peptide after one week in the Y-maze, passive avoidance and novel object tests. Biochemical analyses of the mouse hippocampi showed that OZP002 significantly decreased Aß25-35-induced increases in reactive oxygen species, lipid peroxidation, and increases in Bax, TNFα and IL-6 levels. Immunohistochemically, OZP002 prevented Aß25-35-induced reactive astrogliosis and microgliosis in the hippocampus. It also alleviated Aß25-35-induced decreases in synaptophysin level and choline acetyltransferase activity. Moreover, chronically administered in APPswe mice during 2 months, OZP002 prevented learning deficits (in all tests plus place learning in the water-maze) and increased biochemical markers. This study shows that σ1 PM with high neuropotective potential can be identified, combining pharmacological efficacy, selectivity and therapeutic safety, and identifies a novel promising compound, OZP002.

Prevalence of dental caries, oral hygiene status and treatment needs among seafarers and trainee sailors in the state of Goa, India: a descriptive cross-sectional study.

BACKGROUND: The fixed regimen and strict dietary habits of seafarers and trainee sailors, make them susceptible to several oral diseases. The aim of the study was to assess prevalence of dental caries, oral hygiene status and treatment needs among seafarers and trainee sailors in the state of Goa. MATERIALS AND METHODS: This descriptive, cross-sectional study was carried out from January 2023 to March 2023. After a pilot study, convenience sampling technique was employed to recruit 261 participants. The investigators were standardized and calibrated to record World Health Organization Oral Health Assessment Form (1997) and Oral Hygiene Index-Simplified (OHI-S) which were instrumented in the study. Intra-examiner and inter-examiner reliability scores were recorded using kappa statistics (0.81, 0.83) and (0.83, 0.85), respectively. The data was analysed using descriptive analysis, chi-square test, Mann- -Whitney U test and multivariate linear regression analysis at statistical significance (p ≤ 0.05). RESULTS: The mean ages of seafarers (n = 133) and trainee sailors (n = 128) were 36.41 ± 6.40, and 25.36 ± 7.39, respectively. The prevalence of dental caries among seafarers and trainee sailors was determined to be 59% and 78%, respectively (p = 0.01). The mean OHI-S score of seafarers (1.31 ± 0.68) and trainee sailors (1.53 ± 0.82) was statistically significant (p = 0.015). CONCLUSIONS: Seafarers and trainee sailors demonstrated high caries prevalence and poor oral hygiene status due to their distinctive lifestyle, representing a vulnerable community in terms of oral health.