Suk-SaiYasna (SSY) is a well-documented traditional Thai herbal formula in the Royal Scripture of King Narai’s Traditional Medicine. SSY contains Cannabis sativa leaves as a key ingredient and has traditionally been used to promote sleep, alleviate stress-related symptoms, and stimulate appetite. This study aimed to investigate the neuroprotective effects of SSY in a mouse model of unpredictable chronic mild stress (UCMS)-induced cognitive impairment and explore the underlying mechanisms, particularly antioxidant enzyme pathways. Behavioral tests, including the Y-maze test, novel object recognition test, and Morris water maze test, demonstrated that UCMS-exposed mice exhibited cognitive impairment compared to non-stress mice. However, SSY treatment significantly improved learning and memory performance in UCMS-exposed mice. Mechanistic studies revealed that SSY reduced lipid peroxidation in the hippocampus and frontal cortex, key brain regions affected by chronic stress. Furthermore, UCMS significantly reduced the activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), whereas SSY treatment restored their activity, indicating antioxidative and neuroprotective effects in vivo. Gene expression analysis further revealed that SSY regulates oxidative stress via the Nrf2/Keap1 signaling pathway. In vitro studies using 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay confirmed the radical scavenging activities of SSY and its herbal components, demonstrating significant antioxidant potential. Phytochemical analysis identified delta-9-tetrahydrocannabinol, delta-9-tetrahydrocannabinolic acid A, and cannabinoids as bioactive compounds in SSY, along with potent antioxidants such as gallic acid, myricetin, myristicin, piperine, costunolide, and gingerol. These findings suggest that the SSY formula mitigates UCMS-induced cognitive function through its antioxidant properties via multiple pathways, including radical scavenging activities, modulating the Nrf2-Keap1 pathway, inducing the expression of HO-1, NQO1 mRNAs, and other antioxidant enzymes. This work bridges traditional Thai medicine with modern neuropharmacology.

Postmenopausal women have a higher probability of experiencing cognitive alterations compared to men, suggesting that the decline in female hormones may contribute to cognitive deterioration. Thailand traditionally uses Tri-Kaysorn-Mas (TKM), a blend of three medicinal herbs, as a tonic to stimulate appetite and relieve dyspepsia. Due to its antioxidant and anti-acetylcholinesterase activities, we investigated the effects of TKM (50 and 100 mg/kg/day, p.o., for 8 weeks) on cognitive deficits and their underlying causes in an ovariectomized (OVX) mouse model of menopause. OVX mice showed cognitive impairment in the Y-maze, novel object recognition task (NORT), and Morris water maze (MWM) behavioral tests, along with atrophic changes to the uterus, altered levels of serum 17β-estradiol, and down-regulated expression of estrogen receptors (ERα and ERβ). These behavioral effects were reversed by TKM. TKM decreased malondialdehyde (MDA) levels and mitigated oxidative stress in the brain by enhancing the activity of superoxide dismutase (SOD) and catalase (CAT) and by up-regulating the antioxidant-related gene Nrf2 while down-regulating Keap1. TKM also counteracted OVX-induced neurodegeneration by enhancing the expression of the neurogenesis-related genes BDNF and CREB. The results indicate that TKM extract alleviates oxidative brain damage and neurodegeneration while enhancing cognitive behavior in OVX mice, significantly improving cognitive deficiencies related to menopause/ovariectomy through multiple targets.

The resin extract of Garcinia nigrolineata (GNR-E), a tropical plant used in Southeast Asian traditional medicine, was evaluated for its antidepressant-like effects in a chronic mild stress (CMS) mouse model, with imipramine as a reference drug. GNR-E dose-dependently alleviated CMS-induced anhedonia (sucrose preference test) and behavioral despair (forced swimming and tail suspension tests). Neurochemical analyses revealed that GNR-E increased serotonin (5-HT) and norepinephrine (NE) levels, reduced expression of their transporters (SERT, NET) and receptors (5-HT1A, 1B, 2A, 2C, 7; α2A, 2C) in the frontal cortex and hippocampus, and normalized HPA-axis hyperactivity by lowering serum corticosterone and modulating glucocorticoid receptor (GR) and SGK-1 mRNA expression. In vitro, GNR-E inhibited monoamine oxidase (MAO)-A and -B (Ki = 2.33 and 1.55 µg/mL, respectively). Phytochemical analysis identified xanthones, particularly cowanin, as key constituents. These findings highlight GNR-E’s potential as a novel plant-based antidepressant, warranting further investigation into its active compounds and clinical applications.

Background/Objectives: Unpredictable chronic mild stress exposure is a primary driver of cognitive decline, largely mediated by hypothalamic–pituitary–adrenal (HPA) axis dysregulation and subsequent oxidative neurotoxicity. In traditional Thai medicine, the AYW-KK-04 formulation—a complex polyherbal remedy—has long been utilized as a “Ya Aayu-Wattana” to restore vitality and elemental balance, yet its neurobiological mechanisms remain poorly understood. This study aimed to evaluate the adaptogenic and neuroprotective potential of AYW-KK-04 against cognitive impairment. Methods: Unpredictable Chronic Mild Stress (UCMS)-induced cognitive impairment in a ICR mouse model. Total phenolic and flavonoid contents and antioxidant capacity (ABTS assay) of AYW-KK-04 were determined. Behavioral assessments using Y-maze test, novel object recognition test (NORT), and Morris Water Maze (MWM) test. BDNF, CREB, Nrf and Keap1 mRNA gene expression, SOD and CAT enzymatic activity and lipid peroxidation assay were investigated to clarify the mechanisms of action. Moreover, HPLC chromatography was studied to quantify the active compounds of the AYW-KK-04 formulation. Results: It demonstrated that oral administration of AYW-KK-04 significantly reversed UCMS-induced memory deficits. At the molecular level, AYW-KK-04 effectively upregulated BDNF and CREB mRNA expression in the frontal cortex and hippocampus, suggesting a restoration of synaptic plasticity. Simultaneously, the formulation activated the Nrf2/Keap1 signaling pathway, leading to enhanced SOD and CAT enzymatic activities and a marked reduction in MDA-mediated lipid peroxidation. HPLC analysis confirmed the presence and consistency of key bioactive constituents. Conclusions: These findings suggest that the adaptogenic properties of AYW-KK-04 arise from its dual capacity to reinforce neurotrophic support and bolster the endogenous antioxidant shield, providing a mechanistic support for the traditional use of AYW-KK-04 as an adaptogenic formulation and highlighting its potential as a multi-target intervention for stress-related cognitive dysfunction.