Advances in neuropharmacology: Innovative drug strategies targeting synaptic plasticity, neuroinflammation, and ion channel regulation for future CNS treatments.

Stem cells as emerging regenerative approaches for post-traumatic stress disorder: Mechanisms and translational challenges.

Nitric oxide signaling in Alzheimer's disease: A double-edged sword.

Astrocyte inhibition impacts metaplasticity in the hippocampal CA1 area following traumatic brain injury.

Sulforaphane improved cognitive behavior in APP/PS1 mice via promoting structural and functional synaptic plasticity in the hippocampus.

Musical stimulation can activate specific brain regions and modulate neural functions, whereas optical and magnetic stimulation technologies enable precise neuronal manipulation. However, traditional neural stimulation approaches mostly adopt a single mode, and research on their combined regulatory effects is still limited. Light-magnetic combined stimulation (LMCS), as an emerging multi-modal physical neural modulation technique, has demonstrated unique advantages in regulating neural activity and synaptic plasticity and holds significant potential for application in the fields of cognitive enhancement and neural rehabilitation. This study innovatively combines two physical stimulation modalities-light and magnetic fields-using musical signals as the modulation source to explore their synergistic effects on synaptic plasticity in the hippocampal Schaffer collateral-CA1 region of rats. We designed a high spatial resolution light-magnetic stimulation system; utilizing this system, invitro brain slice experiments were conducted, applying single-light, single-magnetic, and combined light-magnetic stimulation respectively. Changes in long-term potentiation (LTP) and long-term depression (LTD) were recorded. The experimental results showed that the combined light-magnetic stimulation, when synchronized with specific musical rhythms, exhibited the optimal regulatory effects on both LTP and LTD, outperforming single stimulation modes. This study verified the effectiveness of light-magnetic combined stimulation based on music rhythm in regulating LTP/LTD and provided design parameters and experimental basis for the development of the equipment.

A systems-level understanding of Radix Bupleuri-Radix Paeoniae Alba in depression: multi-omics reveals synergistic regulation of Neuroinflammation and synaptic plasticity.

Sleep deprivation (SD) is a critical risk factor for cognitive decline and is closely linked to psychiatric disorders. The hippocampal CA2 region is critically involved in encoding social memory and regulating emotional behavior, and it has been implicated in various neuropsychiatric conditions. However, how SD affects CA2-dependent synaptic plasticity and related behaviors remains poorly understood. Here, we subjected mice to 5 h of SD via gentle handling and examined synaptic plasticity, molecular signaling, and social recognition memory. Electrophysiological recordings revealed that SD markedly impaired long-term potentiation (LTP) in CA2 and disrupted social recognition memory, as evidenced by failure to distinguish novel from familiar conspecifics. These deficits were accompanied by upregulation of adenosine A1 receptors and PDE4A5, along with reduced expression of plasticity-related proteins including PKMζ, ERK, and BDNF. Moreover, caffeine-induced synaptic potentiation was diminished in SD mice, whereas caffeine supplementation reversed both synaptic and behavioral impairments. Together, these findings demonstrate that SD compromises CA2-dependent plasticity and social cognition through adenosine receptor signaling and identify CA2 as a vulnerable, therapeutically relevant region. Targeting adenosine pathways may represent a novel strategy to mitigate sleep loss-related cognitive dysfunction in neuropsychiatric disorders.

The role of NLRP3 inflammasome in opioid-induced neurochemical markers, therapeutic effects, and adverse effects in male mice.

Cognitive impairment represents the most prevalent complication of neurological diseases (NDs), which significantly affects the quality of life in affected patients. Current treatments primarily target neurotransmitter imbalances but do not act on the key pathological events such as Ca2+ dyshomeostasis, oxidative stress, microglia activation, mitochondrial dysfunction and neuroinflammation that occur in the brain of patients with NDs. Therefore, existing treatments fail to stop the progressive cognitive decline in these diseases. Thus, there is a critical need for literature which covers the potential novel therapeutic targets along with their modulators for the effective treatment of cognitive impairment associated with NDs. Recently, transient receptor potential (TRP) channels have emerged as key regulators of these pathological events implicated in ND-associated cognitive impairment. Many preclinical studies have demonstrated that pharmacological modulation of specific TRP channels can improve cognitive function in animal models of NDs. However, clinical translation of TRP channel modulators is still constrained due to a lack of subtype specificity, limited clinical data and difficulties in drug delivery across the blood-brain barrier (BBB). In the present review, we have discussed the structural diversity of TRP channels, their role in regulating synaptic plasticity and cognitive function, and their potential as pharmacological targets for the treatment of cognitive impairment, which can provide a direction for future research in this field.

Scopolamine-induced cognitive impairment in mice models acute cholinergic dysfunction associated with early functional features of Alzheimer's disease (AD). This study evaluated the neuroprotective potential of curcumin-loaded nanoliposomes (Cur-NL), a bioavailable curcumin formulation, using behavioral, molecular, and biochemical approaches. Male mice received oral Cur-NL (250, 500, or 1000 mg/kg) for 30 days, followed by a single intraperitoneal injection of scopolamine (2 mg/kg). Cognitive performance was assessed by the open field test and Barnes maze. Acetylcholinesterase (AChE) activity, acetylcholine (ACh) levels, hippocampal gene expression, and reactive oxygen species (ROS) accumulation were analyzed to investigate underlying mechanisms. Cur-NL significantly improved spatial learning and memory and restored cholinergic balance by normalizing AChE activity and ACh levels. Treatment also attenuated hippocampal neuroinflammation, oxidative stress, and ROS accumulation. Cur-NL modulated genes related to amyloid processing and synaptic plasticity, suppressing App and Bace1 and upregulating Adam10 and Bdnf. Network analyses supported the involvement of cholinergic, inflammatory, and synaptic signaling pathways. These findings indicate that Cur-NL confers multitarget neuroprotection in a scopolamine-induced model and may serve as a candidate for managing early cholinergic-related cognitive decline. Important limitations should be acknowledged: curcumin concentrations in plasma and brain were not quantified, and a free-curcumin comparator was not included. The findings should therefore be interpreted as evidence of efficacy of the tested Cur-NL preparation, not as a comparative demonstration of nano-liposomal superiority over free curcumin. Direct pharmacokinetic and head-to-head comparative studies are required to establish the formulation-specific contribution of nano-liposomal delivery.

Vascular cognitive impairment (VCI) is a prevalent and heterogeneous condition, both clinically and pathophysiologically, that still lacks approved treatment. Peripheral electrical nerve stimulation (PENS) shows promise for VCI management, yet its underlying neurobiological mechanisms are not well understood. VCI was induced in rats via permanent bilateral common carotid artery occlusion. Cognitive function was assessed using the Morris water maze, Y-maze, and novel object recognition. Synaptic plasticity was evaluated through long-term potentiation recordings and Golgi staining. The nucleus tractus solitarius (NTS)-medial septum-hippocampus circuit was dissected using fiber photometry recording, immunofluorescence multiplex labeling, in vivo multichannel recordings, anterograde/retrograde tracing, and chemogenetic manipulation. We found that PENS at Zusanli (ST36) acupoint significantly elevated hippocampal acetylcholine levels, enhanced synaptic plasticity, and rescued spatial and nonspatial memory deficits in VCI rats. Chemogenetic activation of cholinergic neurons in the NTS enhanced the cognitive function of VCI rats, whereas chemogenetic inhibition of these neurons counteracted the cognitive benefits of PENS. The NTS sends cholinergic projections to the hippocampal cornu ammonis 1 region through the medial septum. Specific inhibition of NTSChAT-medial septumChAT-cornu ammonis 1 circuit reversed the enhancement of spatial memory observed in VCI rats treated with PENS, while leaving the nonspatial memory unaffected. Our findings identify the NTS-medial septum-cornu ammonis 1 cholinergic circuit as a critical mechanism mediating PENS-induced reversal of spatial memory deficits in VCI, revealing a novel and spatially selective therapeutic target for VCI.

A specific pilose antler peptide LVLVEAELRE ameliorates cognitive deficits in SAMP8 mice via Celsr2.

Alzheimer's disease (AD) associated with insulin resistance represents a major challenge in sporadic neurodegeneration, where impaired neuronal survival and synaptic plasticity are compounded by aberrant DNA methylation. Epigenetic silencing of Wnt pathway genes under insulin-resistant conditions exacerbates β-amyloid accumulation, tau hyperphosphorylation, and oxidative stress. The present study aimed to establish insulin-resistant AD models and evaluate the mechanistic potential of DNA methyltransferase (DNMT) inhibition, with a specific focus on canonical Wnt/β-catenin restoration. An in vitro AD model was generated by exposing SHSY-5Y cells to streptozotocin (STZ, 400 μM), resulting in elevated DNMT1, Aβ1-42, and sFRP1 levels, alongside reduced β-catenin and survivin expression. Treatment with the DNMT1 inhibitor 5-azacytidine (5-AZA), employed here as a mechanistic probe rather than a therapeutic candidate, reversed these changes, restoring Wnt signaling and attenuating amyloid burden. In vivo, intracerebroventricular administration of STZ (3 mg/kg) in rats induced an insulin-resistant AD-like pathology characterized by cognitive decline, increased pTau and acetylcholinesterase activity, and reduced neuroprotective markers. 5-AZA treatment improved memory and behavior, decreased pTau and AChE levels, and enhanced ADAM10, TREM2, BDNF, and antioxidant activity. Histological analysis further revealed preservation of neuronal layers and structural integrity. Collectively, these findings demonstrate that DNMT inhibition, exemplified by 5-AZA as a mechanistic tool, can mitigate STZ-induced molecular and behavioral alterations by relieving hypermethylation-mediated repression and supporting partial reactivation of canonical Wnt/β-catenin signaling. While 5-AZA itself is not a viable therapeutic option, the results highlight DNMT inhibition as a promising disease-modifying strategy in insulin resistance-associated AD.

Lead is a toxic heavy metal with significant health risks, as maternal lead exposure during pregnancy disrupts fetal neural development through placental transfer, leading to persistent neurological, developmental, and long-term health consequences in the progeny. Lead exposure typically affects the central nervous system, which is especially harmful during fetal development and early infancy. This review emphasizes the impact of early developmental exposure leading to disruption of neurotransmitter mechanisms. Mechanistically, lead disrupts neurodevelopment through various pathways, including alterations in myelin proteins, synaptic function, and neuroinflammatory responses, by interfering with the regulatory action of calcium, as lead mimics and replaces calcium. Alterations caused by lead, particularly in the dopaminergic, cholinergic, glutamatergic, and GABAergic pathways, increase the risk of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and cognitive disabilities in children. Lead is known to induce cellular, molecular, and epigenetic changes that impair neuronal connectivity, synaptic plasticity, and network functionality, ultimately leading to the disruption of neurodevelopmental pathways. The cumulative evidence highlights various aspects of lead neurotoxicity and emphasizes its role in the etiology of neurodevelopmental impairments. Understanding these pathways is critical for early intervention strategies to mitigate the long-term cognitive and behavioral consequences of lead exposure during sensitive developmental periods.

Non-coding RNA regulatory networks in post-stroke neuropsychiatric complications: Mechanisms, delivery strategies, and translational challenges.

Environmental phthalate exposure impairs cognition in aged males by coupling myelin injury to synaptic dysfunction via Nogo-A/S1PR2 signaling.

Decoding MeCP2 in pain: A systematic review of mechanisms, dosage, and clinical implications.

Mechanism of action of REDD1 in depression and its targeted intervention.

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. The integrated stress response (ISR) contributes to impaired synaptic plasticity, neuronal dysfunction, and cognitive deficits in AD. However, research targeting the ISR as a therapeutic strategy for AD remains limited due to insufficient mechanistic insight.ObjectiveThis study aimed to evaluate the effects of 2BAct, an ISR inhibitor, on behavioral symptoms, amyloid-β (Aβ) and tau accumulation, and neuroinflammation in 5xFAD mice.MethodsTen-month-old 5xFAD mice received daily intraperitoneal (IP) injections of either 2BAct (10 mg/kg/day), donepezil (2 mg/kg/day; positive control), or vehicle for 23 consecutive days. Anxiety-like behavior and cognitive function were assessed using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Amyloid-β (Aβ), tau, and neuroinflammation markers were analyzed by immunofluorescence staining. ISR inhibition was evaluated by examining the phosphorylation level of eukaryotic initiation factor 2 alpha (eIF2α) using immunofluorescence staining and by analyzing ISR-related markers via RNA sequencing.Results2BAct treatment significantly improved object recognition performance and attenuated microglial activation and tau accumulation, without reducing Aβ burden. Reduced levels of phosphorylated eIF2α were also confirmed by immunofluorescence staining.ConclusionsThese findings suggest that 2BAct treatment improves cognitive performance and mitigates neuroinflammation while reducing tau accumulation. Although the therapeutic effects are limited, targeting the ISR with inhibitors such as 2BAct represents a potential therapeutic approach for AD. Further studies are required to elucidate the underlying molecular mechanisms and to address the limitations of ISR-based interventions.