Age-related macular degeneration (AMD) is a progressive eye disease that causes irreversible impairment of central vision, and effective treatment is not yet available. Extracellular accumulation of amyloid-beta (Aβ) in drusen that lie under the retinal pigment epithelium (RPE) has been reported as one of the early signs of AMD and was found in more than 60% of Alzheimer’s disease (AD) patients. Extracellular deposition of Aβ can induce the expression of inflammatory cytokines such as IL-1β, TNF-α, COX-2, and iNOS in RPE cells. Thus, finding a compound that can effectively reduce the inflammatory response may help the treatment of AMD. In this research, we investigated the anti-inflammatory effect of the coral-derived compound 4-(phenylsulfanyl) butan-2-one (4-PSB-2) on Aβ_1-42 oligomer (oAβ_1-42) added to the human adult retinal pigment epithelial cell line (ARPE-19). Our results demonstrated that 4-PSB-2 can decrease the elevated expressions of TNF-α, COX-2, and iNOS via NF-κB signaling in ARPE-19 cells treated with oAβ_1-42 without causing any cytotoxicity or notable side effects. This study suggests that 4-PSB-2 is a promising drug candidate for attenuation of AMD.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by an excessive inflammatory response and impaired memory retrieval, including spatial memory, recognition memory, and emotional memory. Acquisition and retrieval of fear memory help one avoid dangers and natural threats. Thus, it is crucial for survival. AD patients with impaired retrieval of fear memory are vulnerable to dangerous conditions. Excessive expression of inflammatory markers is known to impede synaptic transmission and reduce the efficiency of memory retrieval. In wild-type mice, reducing inflammation response can improve fear memory retrieval; however, this effect of this approach is not yet investigated in 3xTg-AD model mice. To date, no satisfactory drug or treatment can attenuate the symptoms of AD despite numerous efforts. In the past few years, the direction of therapeutic drug development for AD has been shifted to natural compounds with anti-inflammatory effect. In the present study, we demonstrate that the compound 4-(phenylsulfanyl) butan-2-one (4-PSB-2) is effective in enhancing fear memory retrieval of wild-type and 3xTg-AD mice by reducing the expression of TNF-α, COX-2, and iNOS. We also found that 4-PSB-2 helps increase dendritic spine density, postsynaptic density protein-95 (PSD-95) expression, and long-term potentiation (LTP) in the hippocampus of 3xTg-AD mice. Our study indicates that 4-PSB-2 may be developed as a promising therapeutic compound for treating fear memory impairment of AD patients.

Depression is a life-threatening psychiatric disorder and a major public health concern worldwide with an incidence of 5% and a lifetime prevalence of 15%–20%. It is related with the social disability, decreased quality of life, and a high incidence of suicide. Along with increased depressive cases, health care cost in treating patients suffering from depression has also surged. Previous evidence have reported that depressed patients often exhibit altered circadian rhythms. Circadian rhythm involves physical, mental, and behavioral changes in a daily cycle, and is controlled by the suprachiasmatic nucleus of the hypothalamus in responding to light and darkness in an environment. Circadian rhythm disturbance in depressive patients causes early morning waking, sleep disturbances, diurnal mood variation, changes of the mean core temperature, endocrine release, and metabolic functions. Many medical interventions have been used to treat depression; however, several adverse effects are noted. This article reviews the types, causes of depression, mechanism of circadian rhythm, and the relationship between circadian rhythm disturbance with depression. Pharmaceutical and alternative interventions used to treat depressed patients are also discussed.

Introduction: Declining spatial working memory (WM) is an early hallmark of Alzheimer's disease (AD). Sleep disturbance exacerbates spatial WM and increases AD risk. The GABAergic system, crucial for sleep regulation, may mediate this link. We thus investigate the relationship between spatial WM and hippocampal GABAergic signaling during rapid eye movement sleep deprivation (REM‐SD) in AD model mice.Methods: We assessed spatial and non‐spatial WM, locomotor activity, and anxiety‐like behavior in 6‐month‐old triple transgenic (3xTg) AD mice and wild‐type (WT) controls, with and without REM‐SD (5 days, 4 h/day). We then used immunofluorescence to quantify GABA_Aα1, GABA_BR1, GAD67, and GABA levels in the prefrontal cortex (PFC) and hippocampus and analyze the correlations with behavioral outcomes.Results: REM‐SD increased locomotor activity, reduced anxiety‐like behavior, and improved non‐spatial WM in 3xTg‐AD mice. Conversely, REM‐SD impaired spatial WM in WT mice, which was also demonstrated in 3xTg‐AD mice. Increased hippocampal GABA levels are correlated with improved non‐spatial WM in 3xTg+SD mice. In contrast, impaired spatial WM in WT+SD mice was associated with elevated hippocampal GABA and GABA_BR1, decreased hippocampal GAD67, and reduced PFC GABA levels. Notably, spatial WM in 3xTg+SD and 3xTg control mice related to increased GABA_Aα1 in the PFC and hippocampus and GAD67 in hippocampal CA1, along with decreased GABA_BR1 and GAD67 in the dentate gyrus.Conclusion: REM‐SD‐induced alterations in WM performance are linked to GABAergic signaling changes in the PFC and hippocampus, with distinct patterns in WT and 3xTg‐AD mice. This study provides insight into AD pathologies and potential therapeutic targets for sleep‐related cognitive impairments.

Stress can elicit glucocorticoid release to promote coping mechanisms and influence learning and memory performance. Individual memory performance varies in response to stress, and the underlying mechanism is not clear yet. Peroxiredoxin 6 (PRDX6) is a multifunctional enzyme participating in both physiological and pathological conditions. Several studies have demonstrated the correlation between PRDX6 expression level and stress-related disorders. Our recent finding indicates that lack of the Prdx6 gene leads to enhanced fear memory. However, it is unknown whether PRDX6 is involved in changes in anxiety response and memory performance upon stress. The present study reveals that hippocampal PRDX6 level is downregulated 30 min after acute immobilization stress (AIS) and trace fear conditioning (TFC). In human retinal pigment epithelium (ARPE-19) cells, the PRDX6 expression level decreases after being treated with stress hormone corticosterone. Lack of PRDX6 caused elevated basal H₂O₂ levels in the hippocampus, basolateral amygdala, and medial prefrontal cortex, brain regions involved in anxiety response and fear memory formation. Additionally, this H₂O₂ level was still high in the medial prefrontal cortex of the knockout mice under AIS. Anxiety behavior of Prdx6^−/− mice was enhanced after immobilization for 30 min. After exposure to AIS before a contextual test, Prdx6^−/− mice displayed a contextual fear memory deficit. Our results showed that the memory performance of Prdx6^−/− mice was impaired when responding to AIS, accompanied by dysregulated H₂O₂ levels. The present study helps better understand the function of PRDX6 in memory performance after acute stress.

Astragaloside IV (ASIV), a natural compound from Astragalus membranaceus, exerts neuroprotective and anti-inflammatory effects in various pathologies. Its role in Plasmodium yoelii (Py) 17XL-induced inflammation leading to blood-brain barrier (BBB) damage remains undefined. Artesunate (ART), the frontline therapy for severe malaria, has encountered resistance and unresolved neurological sequelae. This study investigated the anti-inflammatory properties of ASIV combined with ART in Py-infected mice. Sixty-five Institute of Cancer Research mice were randomized into 5 groups: sham, Py, Py-ART, Py-ASIV, and Py-ASIV + ART. Mice in Py groups were infected with Py 17XL. Either 25 mg/kg ASIV alone or 25 mg/kg ASIV plus 2.4 mg/kg ART was administered intraperitoneally for 5 days. Survival rate/time, parasitemia, neurological status, histopathology, and biochemical indices were evaluated. Although ASIV alone partially suppressed parasitemia, combination therapy significantly prolonged survival and mitigated neurological deficits. Both ASIV and ASIV + ART reduced IL-1β and TNF-α expression in serum and brain, attenuated BBB leakage (Evans blue assay), and preserved BBB integrity by decreasing astrocytic glial fibrillary acidic protein and aquaporin-4 while upregulating the tight junction proteins occludin and zonula occludens-1. ASIV exhibited modest antiparasitic action and robust anti-inflammatory effects, alleviating BBB disruption when combined with ART in Py 17XL-infected mice. These findings provide an essential basis for further preclinical exploration of ASIV as an adjunct therapy in severe malaria.