FRMPD2 is a human-specific multi-copy gene with higher mRNA expression in brain tissue, but its role in synapse formation and neurodevelopment remains unknown. We find that FRMPD2 is a neuron-specific protein with a high expression level in human brains compared to rodent brains. FRMPD2 overexpression in rat neurons stimulates synaptogenesis, leading to increased synaptic activities. Importantly, our results show that FRMPD2 via its PDZ domains recruits and enhances neuroligin-1 protein levels at the postsynaptic sites, and via its FERM domain interacts with the F-actin network in the spine. Increased expression of FRMPD2 also promotes spine formation and maturation, a foundational process for synapse formation. In developing embryonic mouse brains expressing higher FRMPD2 protein levels, we observed delayed neuronal migration, presumably promoting a protracted timeline for cortical lamination as a feature in human brain development. Behaviorally, mice with FRMPD2 overexpression in the brain demonstrate enhanced spatial memory retention. These findings indicate an important function for FRMPD2 in neuronal connectivity, brain development, and cognitive function.

Age-related cognitive impairment is often linked to cholinergic dysfunction and increased oxidative stress. This study explored the neuroprotective potential of lutein-zeaxanthin extract (XanMax® 2002; LZ) through both in vitro and invivo approaches. In vitro, Neuro-2a cells exposed to hydrogen peroxide (H2O2) were treated with LZ (5-20 μg/mL), leading to decreased expression of apoptosis-related proteins. In vivo, memory impairment was induced by scopolamine in C57BL/6N mice, followed by oral administration of LZ (4 or 8 mg/kg) for 4 weeks. Behavioral assessments-including the Morris water maze, Y-maze, and passive avoidance tests-demonstrated significant improvements in spatial learning, working memory, and memory retention in LZ-treated groups, particularly at the higher dose. Biochemical analysis revealed increased acetylcholine levels, reduced acetylcholinesterase activity, and downregulation of oxidative stress and neuroinflammatory markers in brain tissue. Moreover, LZ supplementation upregulated genes associated with synaptic function and memory. The cognitive-enhancing effects of LZ were comparable with those of donepezil. These findings suggest that LZ may exert neuroprotective effects through antioxidant and anti-inflammatory mechanisms and are a potential dietary intervention for cognitive decline.

Mild cognitive impairment (MCI) represents an intermediate stage between normal aging and Alzheimer's disease. This study investigated the neuroprotective effects of a combined extract of Mentha piperita (MP) and Cornus officinalis (CO) (MC) using in vitro and in vivo models. In SK-N-SH cells, pretreatment with MC (50-150 μg/mL) significantly attenuated H2O2-induced cellular injury, as evidenced by a reduction in Annexin V-positive cells and an increase in brain-derived neurotrophic factor (BDNF) mRNA expression. Rosmarinic acid and loganin, the marker compounds of MP and CO, alone or combined at a 6:4 ratio, mitigated H2O2-induced decreases in cell viability and BDNF mRNA. In the in vivo study, male Sprague-Dawley rats were orally administered MC (50, 100, or 200 mg/kg/day) for 28 days, with phosphatidylserine (50 mg/kg/day) serving as a positive control. MC administration significantly improved cognitive performance in rats with scopolamine-induced memory impairment, as demonstrated by increased step-through latency in the passive avoidance test and reduced escape latency in the Morris water maze. Furthermore, in the probe trial, MC-treated rats spent significantly more time in the target quadrant, indicating enhanced spatial memory retention. Mechanistically, MC restored hippocampal acetylcholine levels and reversed the scopolamine-induced decrease in BDNF and its downstream signaling. Specifically, MC upregulated hippocampal BDNF expression and enhanced the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), and cAMP response element-binding protein (CREB). In conclusion, these results demonstrate that the MC extract possesses potent neuroprotective and learning- and memory-enhancing effects, highlighting its potential as a therapeutic candidate for managing age-related cognitive decline and MCI.

IntroductionAlzheimer's disease (AD) is a progressive and prevalent neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. Intracerebroventricular (ICV) administration of streptozotocin (STZ) in rodents recapitulates key features of sporadic AD, including brain insulin resistance and oxidative stress. Dexmedetomidine (Dex), a highly selective α2‐adrenergic receptor agonist, has demonstrated neuroprotective and anti‐inflammatory properties, suggesting its potential utility as a therapeutic approach for AD.MethodsSeventy adult male Wistar rats were randomly allocated to seven experimental groups: Control, Sham, STZ, Sham + Dex (25 µg/kg), and STZ + Dex (25, 50, 100 µg/kg). Cognitive performance and anxiety‐like behaviors were evaluated using the open‐field test (OFT), elevated plus maze (EPM), Y‐maze test, and Morris water maze (MWM).ResultsIn the Y‐maze, STZ‐treated rats exhibited significant reductions in spontaneous alternation behavior (p = 0.002), which were significantly reversed by Dex (25 µg/kg, p = 0.002). In the MWM, the STZ administration resulted in prolonged escape latencies and increased path lengths compared with Control animals (p < 0.05). Treatment with Dex (25 µg/kg) significantly improved spatial learning and memory retention (p < 0.05). No significant differences were observed in locomotor activity and anxiety‐related behaviors in the OFT or EPM.ConclusionsThese findings indicate that Dex at 25 µg/kg attenuates STZ‐induced cognitive deficits, likely through neuroprotective and anti‐inflammatory mechanisms. The results highlight Dex as a promising candidate for AD therapy, though further research is required to elucidate its underlying molecular pathways. The study supports the potential repurposing of Dex for neurodegenerative disorders.

Prenatal nicotine exposure affects hippocampal development and behavior in mouse offspring.

Methamphetamine (METH) is a potent psychostimulant that induces severe neurotoxicity, leading to long-lasting cognitive and affective impairments. Despite its widespread abuse, effective therapeutic strategies for reversing METH-induced neural damage remain limited. Platelet-derived exosomes (pExos) have recently emerged as promising cell-free candidates for neurorestorative therapies. This study aimed to investigate the effect of pExos in a rat model of chronic methamphetamine addiction. Then, 36 male Wistar rats were divided into three experimental groups. The treatment group received METH coadministered with platelet exosomes. After 10 days, a series of behavioral tests were performed to evaluate the treatment's effect on memory, learning, depression, and anxiety-like behaviors. These tests included the Morris water maze, Novel object recognition, Elevated plus maze, and Forced swimming test. The rat hippocampus was evaluated by several methods including Nissl staining, Immunohistochemical assay for Caspase-3, Ki-67, Iba1, and qRT-PCR for Bax and Bcl2 gene expression analysis. Furthermore, the concentrations of IL-1β and TNF-α, as well as the levels of several oxidative stress markers were assessed. Treatment with pExos significantly improved learning, spatial memory retention, and recognition performance in METH-treated rats (P < 0.05). Also, pExos reduced depression and anxiety-like behaviors (P < 0.01). These behavioral enhancements were accompanied by reduced apoptosis, neuronal cell loss, and restoration of hippocampal cell proliferation. Additionally, a reduction in inflammatory cytokines and oxidative stress was demonstrated following exosome therapy (P < 0.01). These findings suggest that pExos offer a multifaceted neuroprotective effect against METH-induced brain injury by modulating apoptosis, inflammation, oxidative stress, and neuronal cell proliferation. Given their safety, accessibility, and efficacy, pExos could be a promising therapeutic platform to address substance-induced neurocognitive disorders.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and neuroinflammation. Synaptic plasticity and neuroinflammation are hallmarks of AD, with their dysregulation forming a self-reinforcing cycle that aggravates neurodegeneration. Proinflammatory cytokines impair synaptic signaling by suppressing brain-derived neurotrophic factor (BDNF) expression and neuroplasticity markers, further compromising synaptic plasticity. β-Caryophyllene (BCP), a natural bicyclic sesquiterpene with anti-inflammatory and neuroprotective properties, may counteract these pathological processes. This study evaluated the effect of BCP in mitigating streptozotocin (STZ)-induced AD-like conditions in male Sprague-Dawley rats. Two doses of STZ (3 mg/kg) on Days 1 and 3 were administered intracerebroventricularly to induce AD-like pathology. Rats received BCP (10, 20 mg/kg, i.p.) or rivastigmine (2.5 mg/kg) for 28 days. Cognitive performance was assessed using the Barnes maze and novel object recognition tests. Hippocampal tissues were analyzed for BDNF expression, synaptic plasticity markers (e.g., synaptophysin, neural cell adhesion molecule [NCAM], and ciliary neurotrophic factor [CNTF]), neuroinflammatory markers (e.g., IL-1β, TNF-α, IL-6, COX2, and NF-κB), and oxidative stress markers. Histological (hematoxylin and eosin) and Golgi-Cox staining techniques were employed to evaluate neuronal integrity and synaptic organization. STZ-induced rats exhibited significant cognitive deficits, synaptic loss, and increased neuroinflammation. BCP treatment improved spatial learning and memory retention, increased BDNF expression, and restored synaptic plasticity markers. Furthermore, BCP attenuated neuroinflammation by reducing proinflammatory cytokine levels. Histopathology confirms normal hippocampal neuronal architecture in BCP-treated groups. These findings highlight the ability of BCP to modulate BDNF signaling, synaptic plasticity, and neuroinflammatory pathways, underscoring its potential as a multitarget therapeutic candidate for AD.

Traumatic brain injury (TBI) disrupts the blood–brain barrier (BBB), resulting in increased permeability, neuronal loss, and cognitive dysfunction. This study investigates the therapeutic potential of thyroid hormone (T4) to reduce BBB dysfunction following moderate fluid percussion injury. T4 injection (intraperitoneal) after TBI restores the levels of pericytes and endothelial cells vital for BBB integrity, reduces edema by downregulating AQP-4 gene expression, and enhances levels of the tight junction protein ZO-1. T4 counteracts the TBI-related increase in MMP-9 and TLR-4, significantly reducing BBB permeability. Furthermore, T4 enhances the neuroprotective functions of astrocytes by promoting the activity of A2 astrocytes. Additionally, T4 treatment increases DHA levels (important for membrane integrity and function), stimulates mitochondrial biogenesis, and leads to a notable improvement in spatial learning and memory retention. These findings suggest that T4 has significant potential to reduce vascular leakage and inflammation after TBI, thereby improving cognitive function and maintaining BBB integrity.

Age-related cognitive decline and synaptic loss are associated with alterations in hippocampal synaptic protein phosphorylation and signaling pathways. Natural compounds from marine sources, such as Capsosiphon fulvescens glycopeptides (Cf-tPep), have shown potential neuroprotective properties. This study aimed to investigate the effects of trypsinized glycopeptides from C. fulvescens on synaptic protein phosphorylation and cognitive function in aging hippocampal neurons and rats. The research employed both in vitro and in vivo experimental models to evaluate the impact of Cf-tPep on aged hippocampal neurons and cognitive function in rats. Primary hippocampal neurons from rats were cultured for 49days to model aging. Synaptic protein expression and phosphorylation were analyzed through Western blotting, immunoprecipitation, and double-immunofluorescence. In vivo, aged rats received Cf-tPep via hippocampal microinjection using osmotic pumps. Cognitive function was assessed using the Morris water maze test. Cf-tPep treatment restored phosphorylation levels of synaptic proteins, including PSD95 (S295) and GluN2B (Y1472), in aged neurons. This effect was mediated through inhibition of the calcineurin-STEP signaling pathway and activation of CaMKII-ERK1/2 signaling, enhancing synaptic plasticity and reducing neuronal senescence. In aged rats, Cf-tPep improved spatial learning and memory retention by modulating synaptic protein phosphorylation. Trypsinized glycopeptides from C. fulvescens show promise as a therapeutic agent for alleviating age-related cognitive decline through regulation of synaptic signaling pathways. These findings suggest their potential for promoting brain health in the elderly.

Background: Traumatic brain injury (TBI) disrupts blood supply, damages neurons and glial cells, and reduces local activation of the prohormone thyroxine (T4) to the active form, triiodothyronine. We treated mice with T4 post-TBI to evaluate the role of thyroid hormone in neural cell protection and injury recovery after TBI, especially the effects on neuroglial cells. Materials and Methods: A T4 dose was given 1 hour after controlled cortical injury, and in some groups, an additional T4 dose was given 5 days post-TBI. We analyzed the reactive astrocytes and activated microglia in the ipsilateral cortex. We assessed cortical gliogenesis, with or without T4 treatment, in live animals using 5-ethynyl 2'-deoxyuridine-labeling. Finally, learning and spatial memory retention were tested using the Morris water maze (MWM). Results: T4 treatment 1-hour post-TBI significantly reduced the number of reactive astrocytes and activated microglia in the ipsilateral cortical area. An additional dose of T4 on day 5 post-TBI further reduced the number and size of reactive astrocytes. T4 treatment induced gliogenesis 2.6-fold greater than with saline treatment. T4 treatment induced neuron-glia antigen 2-expressing glial cell proliferation but not astrocytes. Mice treated with T4 post-TBI had improved MWM performance, better escape latency, and better spatial memory compared with saline-treated mice. Conclusion: Our data indicate that T4 treatment shortly after TBI significantly reduced acute astroglial cell activation and improved recovery of neurons and brain function.

Deviations in neuropsychological development in the adolescence are considered in a pediatric clinic as the first peak of deviations with possible suicidal acts, and in the early adulthood - as a second peak their manifestations. The influence of the serotonin reuptake inhibitor fluoxetine in the infantile period (P25-P39) was studied in rats subjected to inflammatory pain in the neonatal period, on cognitive function and the reactivity of the hypothalamic-pituitary-adrenal (HPA) axis in juvenile period (P54-P63), which correspond to the listed age periods in humans. Fluoxetine did not affect the spatial memory of control rats of both sexes and normalized the memory of the first day impaired by inflammatory pain in females; combination of pain and fluoxetine worsened long-term memory in females in comparison with males and in comparison with memory of the first day; shorter retention of spatial memory in females compared to males was associated with lower HPA axis reactivity. Our findings suggest that the effect of fluoxetine on the integrative function of the brain and reactivity of the HPA axis in the juvenile period depends on rat sex and neonatal pain.

Lipopolysaccharide (LPS), a bacterial endotoxin that has been widely used in experimental neuroscience to model neuroinflammation and its effects on cognitive functions. This study investigates the dose-dependent impact of LPS-induced neurotoxicity on memory processing and alertness in Wistar rats. 20 Wistar rats were randomly divided into four groups: Control, Low-Dose LPS, Medium-Dose LPS, and High-Dose LPS. The animals underwent behavioral assessments using the Barnes Maze, Object Recognition Test (ORT), and Navigational Maze to evaluate memory and alertness. Results indicated that increasing LPS doses led to a progressive decline in memory performance and alertness. The Barnes Maze test showed that spatial learning and memory retention were significantly impaired in the Medium and High-Dose groups compared to controls. The Object Recognition Test revealed that discrimination indices decreased in a dose-dependent manner, indicating deficits in object recognition memory. Similarly, the Navigational Maze test demonstrated reduced exploratory activity and longer escape latencies in LPS-treated rats, suggesting compromised alertness. Biochemical analyses showed elevated levels of nitric oxide (NO) and interleukin-6 (IL-6) in brain tissues of LPS-treated rats, correlating with cognitive impairments. Histopathological examination of the hippocampus revealed neuronal damage, with the highest degree of neurodegeneration observed in the High-Dose LPS group. These findings suggest that LPS-induced neurotoxicity disrupts cognitive functions in a dose-dependent manner, with higher doses exacerbating memory and alertness deficits. The results contribute to understanding the role of neuroinflammation in cognitive decline and provide insights into potential therapeutic strategies for neurodegenerative diseases characterized by chronic inflammation, such as Alzheimer's disease.

Oxidative stress is crucial in the pathogenesis of cognitive impairment and neurodegenerative diseases. Epicatechin, a natural flavanol abundant in cocoa, is a promising neuroprotective agent because of its antioxidant and anti-inflammatory properties. This meta-analysis aimed to evaluate the efficacy of epicatechin in mitigating oxidative stress-induced cognitive impairment in animal models. A systematic review of in vivo rodent studies was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, including studies reporting cognitive- and brain-based biochemical outcomes following epicatechin administration. The results indicated that epicatechin significantly improved the cognitive performance of rodents in the Morris water maze test, including improved spatial learning (reduced escape latency), memory retention (increased time spent in the target quadrant), and memory precision (increased island crossings). At the molecular level, epicatechin treatment increased the expression or activity of superoxide dismutase, catalase, and nuclear factor erythroid 2-related factor 2 and reduced the levels of nitric oxide, malondialdehyde, tumor necrosis factor-alpha, and interleukin-1 beta. These findings support the role of epicatechin in enhancing antioxidant defense and modulating neuroinflammation. Collectively, the results highlight that epicatechin has the therapeutic potential for preventing or mitigating oxidative stress-related cognitive dysfunction.

Radiotherapy is a prevalent therapeutic modality for head and neck malignancies; however, it invariably results in radiation-induced damage to normal cerebral tissue, culminating in radiation-induced brain injury (RBI). Despite extensive research on radiation-induced neuroinflammation, the association between RBI and the Th17 cell differentiation pathway remains inadequately understood. C57BL/6 mice underwent a single administration of 30 Gy cranial irradiation to develop the RBI model. Cognitive function was evaluated through the Morris water maze (MWM), open field test, novel object recognition test, and rotarod test. Histopathological alterations in brain tissue were analyzed using hematoxylin and eosin (H&E) staining. Immunofluorescence staining was employed to assess the activation of microglia (IBA-1) and astrocytes (GFAP). RNA sequencing was conducted to identify differentially expressed genes, while Simple Western and qPCR were utilized to examine key signaling molecules involved in Th17 cell differentiation. RBI mice demonstrated marked cognitive deficits, particularly in spatial learning and memory retention. Histological examination indicated activation of microglia and astrocytes within the cortex and hippocampus of irradiated mice. RNA sequencing analysis identified a significant enrichment of the Th17 cell differentiation pathway in the cortex of the RBI group. Further validation through Simple Western and qPCR analyses confirmed the upregulation of TGF-β, IL-6, RORγt, IL-17, and P-STAT3 in the cortex of RBI mice. These findings suggested that the Th17 cell differentiation pathway played a pivotal role in the pathogenesis of radiation-induced brain injury. Neuroinflammation mediated by Th17 cells may be a critical mechanism underlying radiation-induced cognitive dysfunction.

Synergistic impact of early-life stress and prenatal immune activation on spatial memory and oxidative metabolism in rat cortico-limbic networks.

Background: Spatial memory is one of the necessary components of our typical day-to-day life. Therefore, its impairment should be alleviated or prevented. The purpose of this study was to assess the effects of swimming exercise on spatial memory performance and hippocampal oxidative stress in male Long-Evans rats with colchicine-induced memory impairment. Methods: Thirty male aged 8 standard deviation (2) weeks; weight 225 (75) gm Long-Evans rats were assigned to normal control, sham control, colchicine control, pre colchicine swimming exercise and post colchicine swimming exercise groups. A memory-impaired rat model was established by administering colchicine intrahippocampally. Swimming exercise was performed before and after spatial memory impairment. For spatial reference and working memory performance evaluation, the Morris water maze test was used. Hippocampal malondialdehyde and glutathione peroxidase were estimated for oxidative stress assessment in all rats. Results: Intrahippocampal colchicine administration significantly impaired spatial memory, and elevated malondialdehyde, decreased glutathione peroxidase level in the hippocampus of colchicine control rats. In contrast, both pre- and post-treatment with swimming exercise significantly improved learning and spatial memory retention and attenuated oxidative damage to nearly normal levels. Conclusion: Swimming exercise prevents as well as alleviates colchicine-induced spatial memory impairment along with hippocampal oxidative stress in male Long-Evans rats. Moreover, this swimming exercise schedule is sufficient to reverse these alarming consequences to almost normal.

Effect of androgen receptor blockade on spatial memory in young and aged male rats in the Barnes maze.

Background: Maternal overnutrition critically influences offspring's long-term metabolic and cognitive health. While prior research indicates maternal diet can disrupt hippocampal function, the specific impact on spatial memory remains unclear. Methods: Female mice were fed a high-fat diet (HFD) for nine weeks before and during pregnancy. Offspring were weaned onto a standard diet and tested at postnatal day 90 using the dry maze, a spatial reference memory task. Results: HFD-exposed offspring exhibited significant learning acquisition impairments, with prolonged latencies in locating hidden rewards and diminished within-session improvements compared to controls. During the probe trial, they spent significantly less time in the target quadrant, indicating long-term spatial memory retention deficits. Notably, these cognitive impairments occurred independently of body weight differences at testing. Discussion: This study uniquely demonstrates that maternal HFD exposure induces specific spatial memory deficits in adult offspring, potentially through neurodevelopmental alterations preceding metabolic dysfunction. The results highlight the importance of prenatal nutrition in shaping cognitive outcomes later in life. Conclusions: These findings extend our understanding of how prenatal nutrition impacts cognitive aging and disease susceptibility. Given rising obesity rates among women of reproductive age, this research underscores the urgent need for targeted interventions to mitigate the intergenerational effects of maternal overnutrition on brain function.

Background: Drug treatment for Spatial memory impairment has a wide range of adverse effects. Objective: To assess the effects of climbing exercise (CE)on spatial memory performance and hippocampal oxidative stress in colchicine induced memory impaired rats. Methods: Thirty male Long-Evans rats (8±2weeks; 225±75 gm)were grouped (6 rats/group)into normal control, sham control, colchicine control, pre colchicine CE and post colchicine CE. In CE, each rat performed 08 to 12 climbs/hour in a climbing tool for consecutive 28 days. Then, reference memory (RM) [Mean escape latency (EL) in acquisition phase, average EL of 5th and 6thacquisition days; number of target crossing (TC) and time spent in target (TT) in probe trial] and working memory (WM) [Mean EL and savings in training and test phase] were assessed by Morris water maze (MWM) test. Then, after sacrifice, hippocampal malondialdehyde (MDA) and glutathione peroxidase (GPx) were estimated. Data were expressed as mean±SEM and analyzed by one way ANOVA followed by Bonferroni’s post hoc test where p£0.05 was considered as statistically significant. Results: This study indicate that intrahippocampal colchicine administration significantly impaired spatial memory, and elevated MDA, decreased GPx level in hippocampus of colchicine control rats. In contrast, both pre and post treatment of CE significantly improved spatial memory retention and attenuated the oxidative damage almost to normal. Conclusion:CE is equally effective in prevention as well as alleviation of colchicine induced spatial memory impairment along with hippocampal oxidative stress in male Long-Evans rats. J Bangladesh Soc Physiol 2024;19(1): 9-22

NLRP3 Inhibitor Alleviates Glycemic Variability-Induced Cognitive Impairment in Aged Rats with Type 2 Diabetes Mellitus