Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder of the elderly characterized by cognitive decline that involves diverse pathological processes. Aging, modulating neuronal instability, is the primary risk factor AD, resulting in dementia, for which a crucial neuropathological feature is the accumulation of amyloid-β (Aβ) plaques wherein suppression of neurosteroids plays important roles. Neurosteroidogenesis gradually decreases during aging, and the regulation of neurosteroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. We demonstrate that treatment with all-trans retinoic acid (atRA, 20 mg/kg, 12-weeks) in humanized Aβ knock-in (hAbKI) mice (11-month old) resulted in increases in hippocampal StAR and sex neurosteroid (estradiol-17β/(E2) in females and testosterone in males) levels, when compared with controls. Elevated StAR and sex neurosteroid levels were associated with reductions in not only Aβ accumulation but also toxic soluble Aβ1-40 and Aβ1-42 peptides in both sexes, emphasizing an inverse correlation between neurosteroidogenesis and AD pathogenesis. Notably, atRA was capable of ameliorating cognitive impairments in both female and male hAbKI mice, as evaluated by Morris Water Maze analyses. These findings provide insights into the mechanistic events by which atRA restores neurosteroid instability, reduces neurotoxicity, and alleviates cognitive impairments in sex-specific hAbKI mice, demonstrating that retinoid therapy could serve as a novel target for the management of AD-related dementia for healthy aging.

In recent years, the number of studies on acupuncture intervention for anxiety disorders has been gradually increasing, and its application scope in clinical practice has also been expanding. This article intends to review and discuss the combination of common acupoints, specific operation methods, efficacy evaluation indicators, clinical effects and potential mechanisms of action. Available evidence suggests that acupuncture may influence anxiety-related symptoms through multiple neurobiological pathways, including autonomic regulation, neurotransmitter signaling, neuroendocrine regulation, and neuroplasticity-related mechanisms; however, the causal contribution of individual pathways remains incompletely established. However, there are still some shortcomings in relevant studies, such as limited sample size, lack of uniformity in efficacy criteria, and relatively insufficient follow-up time. Future research should pay more attention to the application of evidence-based medicine methods, strengthen the discussion of mechanisms of action, and try to establish more individualized intervention plans.

Neuropathic pain arises from complex pathological processes involving oxidative stress and neuroinflammation. Excessive production of reactive oxygen species (ROS) contributes critically to the initiation and persistence of neuropathic pain following nerve injury and inflammatory insults, and antioxidant-based interventions have shown consistent efficacy across multiple preclinical models. This study investigated the analgesic effects of 4-(phenylsulfanyl)butan-2-one (4-PSB-2), a compound with known anti-inflammatory properties, using the chronic constriction injury (CCI) rat model. Intrathecal administration of 4-PSB-2 significantly alleviated CCI-induced thermal hyperalgesia and mechanical allodynia from postoperative days 3 to 28, without affecting baseline nociceptive responses in naïve rats. In the ipsilateral spinal cord dorsal horn (SCDH), 4-PSB-2 reduced oxidative stress, evidenced by decreased expression of tyrosinase and nitrotyrosine, particularly in astrocytes. Additionally, 4-PSB-2 modulated the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway, as demonstrated by enhanced nuclear expression of Nrf2 and upregulation of HO-1 expression, along with reduced Kelch-like ECH-associated protein 1 (Keap1), phosphorylated P38 (p-P38), and tumor necrosis factor-alpha (TNF-α) levels. Glial cell activation was also attenuated. Notably, co-administration with zinc protoporphyrin (ZnPP), a pharmacological inhibitor of heme oxygenase activity, attenuated the analgesic, antioxidant, and anti-inflammatory effects of 4-PSB-2, suggesting that activation of the Nrf2/HO-1 pathway contributes to the protective effects of 4-PSB-2. These findings indicate that 4-PSB-2 confers sustained neuropathic pain relief by regulating oxidative stress and neuroinflammation via astrocytic Nrf2/HO-1 pathway activation, highlighting its potential as a promising therapeutic candidate for neuropathic pain management.

Glyceryl tribenzoate (GTB) or tribenzoin is a flavoring agent with characteristic anti-microbial property. We have already delineated GTB's immunomodulatory role via the enrichment of regulatory T cells in mouse models of multiple sclerosis and anti-neuroinflammatory role via the reduction of glial activation in a monkey model of Parkinson's disease and a mouse model of Huntington's disease. However, its role has never been explored in Alzheimer's disease (AD), the most common neurodegenerative disorder in human. This study underlines the importance of GTB in promoting the growth and function of hippocampal neurons via upregulation of plasticity-associated genes, enrichment of dendritic spines and stimulation of inotropic calcium influx. Accordingly, oral GTB improved hippocampal plasticity and protected memory and learning in 5xFAD mice. Similarly, GTB treatment also reduced cerebral plaque load and increased the life span of aged 5xFAD mice. Interestingly, we observed that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, served as a receptor of GTB. Consequently, GTB was shown to improve hippocampal plasticity and increase cognitive functions in 5xFAD, but not 5xFAD/Ppara-null, mice, indicating an important role of PPARα in GTB-mediated neuroprotection. These results suggest that oral GTB may have therapeutic importance for improving hippocampal functions in AD patients.

Motion sickness (MS) is a prevalent and debilitating vestibular disorder with limited therapeutic options, yet the cortical mechanisms governing individual susceptibility remain elusive. Using a biaxial rotation mouse model, we investigated the role of the anterior cingulate cortex (ACC) in MS by integrating morphology, calcium imaging, electrophysiology, cell ablation, chemogenetics, and optogenetics. Biaxial rotation induced hypothermia, anorexia, taste avoidance, locomotor hypoactivity, and gait incoordination. ACC pyramidal neurons exhibited enhanced activation and increased intrinsic excitability following vestibular stimulation. Ablation of ACC CaMKII[+] neurons alleviated MS symptoms, and bidirectional chemogenetic manipulation demonstrated that ACC glutamatergic projection neurons are both necessary and sufficient for MS behaviors. Furthermore, the ACC to medial vestibular nuclei parvicellular part (MVePC) projection was identified as a previously uncharacterized cortico-vestibular circuit that bidirectionally mediates MS susceptibility. Whole-brain projectome analysis further revealed anatomically heterogeneous projection subtypes of ACC-medial vestibular neurons. These findings advance our understanding of the cortical mechanisms underlying MS and establish the ACC-MVePC pathway as a mechanistic entry point for future neuromodulatory strategies.

Proteins α-, β-, and γ-synuclein in brain distributed predominantly in presynaptic terminals suggesting their role in regulating neurotransmitter release and signal transduction. Misfolded α-synuclein is involved in the pathology of Parkinson's disease which is characterized by the loss of dopaminergic neurons and the resulting dopamine deficiency. The role of synucleins in the physiology of dopamine-controlled signal transmission is still not fully understood. Using acute brain slices from transgenic mice with α-, β-, γ-synuclein knockout (KO) we studied the effect of synuclein deficiency on dopamine and glutamate-induced calcium signals in neurons and astrocytes. We have found that lack of α- or γ -synuclein decreases the dopamine-induced calcium signal in neurons while γ- or αβγ-KO were characterized by a lower calcium signal in response to glutamate. The ability of dopamine to reduce glutamate-induced calcium signal were altered by γ- and αβγ-synuclein deficiency. Monoamine oxidase-dependent dopamine-induced calcium signal in astrocytes was increased in α-synuclein KO brain slices. αβγ-synuclein deficiency had no effect on mitochondrial Ca[2+]-transport and only γ-synuclein KO led to decrease in the rate of mitochondrial calcium uptake and mitochondrial calcium capacity. Thus, synuclein deficiency alters dopamine- and glutamate -induced calcium signalling in neurons and astrocytes.

Serotonin transporter (SERT), encoded by SLC6A4, is a key regulator of serotonergic neurotransmission and a primary target for selective serotonin reuptake inhibitors (SSRIs). Dysregulation of SERT is implicated in neuropsychiatric and neurodevelopmental disorders, including autism spectrum disorder (ASD). SSRIs, while widely used, have limitations such as adverse effects, drug-drug interactions, and interindividual variability, necessitating safer and mechanistically distinct SERT modulators. This study utilized an integrative in-silico approach to evaluate the SERT inhibitory potential of glabridin, glabrene, and liquiritigenin the phytoestrogens from Glycyrrhiza glabra (licorice), known for neuroprotective properties. Blind and site-specific molecular docking, molecular dynamics simulations, binding free energy calculations, ADMET profiling, and machine learning-based QSAR modeling were employed to characterize ligand-transporter interactions. The compounds glabridin and glabrene exhibited favorable binding affinity for the central S1 substrate-binding site of human SERT, with a comparable or superior binding free energy (-50.35 kcal/mol and -52.41 kcal/mol, respectively) to the reference SSRI paroxetine (-53.04 kcal/mol). The 100 ns MD simulations confirmed stable ligand occupancy and persistent interactions with key residues involved in extracellular gate regulation, stabilizing the SERT outward-open inhibitory conformation. ADMET predictions indicated favorable pharmacokinetic properties, including blood-brain barrier permeability and acceptable toxicity profiles of glabridin and glabrene. QSAR-derived IC50 estimates and combination modeling revealed nonantagonistic, mild positive cooperativity between glabridin and glabrene, supported by dual-ligand docking and MM-GBSA analyses, suggesting complementary orthosteric engagement. These findings position glabridin and glabrene as putative natural SERT modulators, providing a mechanistic basis for their potential use in serotonergic modulation therapeutics, warranting further experimental validation.

Alzheimer's disease is a multifactorial disease characterized by proteinopathy caused by senile plaques and neurofibrillary tangles, leading to neuroinflammation and neuronal damage. Bacopa monnieri, with its extensive usage in the Indian traditional medicinal system, Ayurveda, holds promise in enhancing memory and improving neuronal functions. We performed quantitative phosphoproteomics analysis to understand the temporal dynamics of protein phosphorylation involved in Bacopa monnieri-mediated neuroprotection in the Alzheimer's disease model of IMR-32 cells. The quantitative phosphoproteomics analysis identified 5488 phosphopeptides corresponding to 1427 phosphoproteins. Among the dysregulated peptides in the Aβ42 treatment group, 430 were significantly hyperphosphorylated, and 540 were significantly hypophosphorylated. In contrast, the Bacopa monnieri co-treatment group exhibited 64 significantly hyperphosphorylated peptides and 69 significantly hypophosphorylated peptides. The phosphoproteins altered by Aβ42 were involved in biological functions such as RNA splicing, neuron axonogenesis in the central nervous system, and positive regulation of tau-protein kinase activity. Bacopa monnieri restored key pathways altered by Aβ42, including RNA metabolism, cellular response to stress, signaling by Rho GTPases, and RHOBTB2 GTPase cycle. Kinase mapping of differentially expressed phosphoproteins using the KinMap tool identified CDK11B, CDK12, PRKAA1, PRPF4B, STK10, ROCK1 and ROCK2 as downstream effectors of Bacopa monnieri. The network analysis of restored proteins revealed tight interactions between proteins associated with splicing regulation and stress response. This study offers a comprehensive understanding of phosphoproteome alterations involved in Alzheimer's disease in response to neuroprotection by Bacopa monnieri, which may pave the way for developing therapeutic strategies.

The NKCC1 cotransporter mediates chloride influx into neurons, playing a crucial role in maintaining chloride homeostasis. An increase in NKCC1 raises intracellular chloride concentration, which shifts the polarity of inhibitory synaptic potentials mediated by GABA and glycine towards depolarization. NKCC1 levels are upregulated in certain neurological diseases and psychiatric disorders associated with neuronal hyperactivity. However, the response of NKCC1 in motoneurons following nerve injury, as well as the influence of target-derived neurotrophic factors on this cotransporter, has been scarcely investigated. Here, we have addressed these questions using the oculomotor system as the experimental model. In particular, we evaluated the changes in NKCC1 levels induced by axotomy in extraocular motoneurons, as well as the effects of administering VEGF or BDNF. For this purpose, we performed monocular enucleation of adult rats to induce axotomy of extraocular motoneurons and used immunofluorescence at the confocal microscopy level for image analysis. Our time course study demonstrated that NKCC1 was upregulated in axotomized motoneurons, reaching a maximum at 15 days post-lesion. An interesting finding was that the administration of VEGF prevented this upregulation. BDNF delivery resulted in NKCC1 levels intermediate between control and axotomy. Axotomized motoneurons also showed an increase in soma size that was prevented by administration of VEGF, but not BDNF, consistent with the ability of NKCC1 to transport water into the cell along with ions. The present data suggest that VEGF may have therapeutic potential for neuronal diseases or injuries characterized by increased NKCC1 expression and associated hyperactivity.