Memory Impairment Research Articles

Electroacupuncture improves diabetic cognitive impairment rats by suppressing NLRP3 inflammasome activation via induction of mitophagy

Diabetic cognitive impairment pose a significant threat to public health in our aging society. However, the underlying molecular mechanisms have not been fully elucidated, which warrants further investigation. This study aimed to investigate the effects of electroacupuncture on cognitive impairment and its associated mechanisms. The diabetes model was induced via intraperitoneal injection of streptozotocin (STZ) into Sprague-Dawley rats combined with a high-fat and high-sugar diet. The learning and memory abilities of the rats were assessed using behavioral tests. Electron microscopy and hematoxylin-eosin (H&E) staining were used to identify the histological changes of neurons in the CA1 area of the rat hippocampal CA1. An examination of related indicators was performed by Western blotting including NLRP3 inflammasome-associated proteins Caspase-1, IL-18, IL1β, NLRP3, and P62, and mitophagy-related proteins Pink1, LC3, and Parkin. After modeling, rats displayed impaired learning and memory functions. The administration of electroacupuncture treatment alleviated diabetic cognitive impairment, described as shorter escape latency and an increased frequency of platform crossings. The damaged morphological and ultrastructural changes of neurons in rat hippocampal CA1 area can be alleviated through electroacupuncture treatment. Furthermore, in-depth studies suggest that electroacupuncture treatment can suppress NLRP3 inflammasome activation through induction of Pink1, LC3 and Parkin expression. Electroacupuncture treatment can attenuate NLRP3 inflammasome activation by promoting mitophagy, eventually improving cognitive impairment in (STZ)-treated rats with a high-fat die.

Electroconvulsive Therapy, Manufacturers' Liability, and Learned Intermediaries.

Manufacturers of drugs or devices that are prescribed by physicians are protected by the "learned intermediary rule" from having to disclose risks directly to patients. Instead, they must inform physicians of these risks. But when a company fails to disclose a known risk, how can a patient gain compensation for any resulting harm? The California Supreme Court considered this question in a case involving alleged memory impairment from electroconvulsive therapy. By broadening the ways by which plaintiffs can demonstrate that the absence of a warning caused their injury, the court made it easier for patients to recover compensation for the consequences.

Efficacy and safety of deep brain stimulation in drug resistance epilepsy: A systematic review and meta-analysis.

In the context of drug-resistant epilepsy, deep brain stimulation (DBS) has received FDA approval. However, there have been reports of potential adverse effects, such as depression and memory impairment associated with DBS.This systematic review and meta-analysis aimed to investigate the impact of DBS on the quality of life (QoL), and seizure frequency of patients who had DRE, and assess its potential adverse events. The study followed PRISMA guidelines and thoroughly assessed databases, including Pubmed, Scopus, Embase, Web of Science, and the Cochrane Library, up to 31 July. Statistical analysis, fixed effect model analysis, performed by the Comprehensive Meta-analysis software (CMA) version 3.0. Additionally, Cochran's Q test was conducted to determine the statistical heterogeneity. The systematic review encompassed 54 studies, with 38 studies included in the subsequent meta-analysis. The total number of patients included in the studies was 999. The findings indicated a significant decrease in the mean seizure frequency of subjects following DBS (SMD: 0.609, 95% CI: 0.519 to 0.700, p-value < 0.001). Moreover, patients' QoL significantly improved after DBS (SMD: -0.442, 95% CI: -0.576 to -0.308, p-value < 0.001). The hippocampus displayed the most notable effect size among the different DBS targets. Subgroup analysis based on follow-up duration revealed increased DBS efficacy after two years. There are few reports of adverse events, such as insertional-related complications, infection, and neuropsychiatric complications, but the majority of these were temporary and non-fatal. DBS emerged as an effective and safe procedure for reducing seizure frequency and enhancing the quality of life in DRE patients, with minimal adverse events. Furthermore, the efficacy of DBS was observed to improve over time.

Temporal atrophy together with verbal encoding impairment is highly predictive for cognitive decline in typical Alzheimer's dementia - a retrospective follow-up study.

The increasing prevalence of Alzheimer's disease (AD) has created an urgent need for rapid and cost-effective methods to diagnose and monitor people at all stages of the disease. Progressive memory impairment and hippocampal atrophy are key features of the most common so-called typical variant of AD. However, studies evaluating detailed cognitive measures combined with region of interest (ROI)-based imaging markers of progression over the long term in the AD dementia (ADD) stage are rare. We conducted a retrospective longitudinal follow-up study in patients with mild to moderate ADD (aged 60-92 years). They underwent magnetic resonance imaging (MRI; 3 Tesla, MPRAGE) as well as clinical and neuropsychological examination (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] -Plus test battery) at baseline and at least one follow-up visit. ROI-based brain structural analysis of baseline MRIs was performed using the Computational Anatomy Toolbox (CAT) 12. Clinical dementia progression (progression index [PI]) was measured by the annual decline in the Mini Mental State Examination (MMSE) scores. MRI, demographic, and neuropsychological data were included in univariate and multiple linear regression models to predict the PI. 104 ADD patients (age 63 to 90 years, 73% female, mean MMSE score 22.63 ± 3.77, mean follow-up 4.27 ± 2.15 years) and 32 age- and gender-matched cognitively intact controls were included. The pattern of gray matter (GM) atrophy and the cognitive profile were consistent with the amnestic/typical variant of ADD in all patients. Deficits in word list learning together with temporal lobe GM atrophy had the highest predictive value for rapid cognitive decline in the multiple linear regression model, accounting for 25.4% of the PI variance. Our results show that temporal atrophy together with deficits in the encoding of verbal material, rather than in immediate or delayed recall, is highly predictive for rapid cognitive decline in patients with mild to moderate amnestic/typical ADD. These findings point to the relevance of combining detailed cognitive and automated structural imaging analyses to predict clinical progression in patients with ADD.

Spontaneous cerebrovascular reactivity at rest in older adults with and without mild cognitive impairment and memory deficits.

Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment. One hundred sixty-one older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's disease (AD) biomarkers, and brain magnetic resonance imaging. Spontaneous CVR was quantified during 5 minutes of rest. Respiratory gases analyzed through nasal cannula to quantify end-tidal carbon dioxide (ETCO2) levels were used to estimate CVR. Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for AD biomarkers and vascular risk factors. Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, suggesting medial temporal microvascular dysfunction is observed in cognitive decline. Aging is associated with decline in whole brain spontaneous cerebrovascular reactivity (CVR). Older adults with mild cognitive impairment exhibit deficits in spontaneous CVR in the parahippocampal gyrus (PHG). Memory impairment is correlated with reduced spontaneous CVR in the PHG.

Disruption of the autism-associated Pcdh9 gene leads to transcriptional alterations, synapse overgrowth, and defective network activity in the CA1.

Protocadherins, a family of adhesion molecules with crucial role in cell-cell interactions, have emerged as key players in neurodevelopmental and psychiatric disorders. In particular, growing evidence links genetic alterations in Protocadherin 9 (PCDH9) gene with Autism Spectrum Disorder (ASD) and Major Depressive Disorder (MDD). Furthermore, Pcdh9 deletion induces neuronal defects in the mouse somatosensory cortex, accompanied by sensorimotor and memory impairment. However, the synaptic and molecular mechanisms of PCDH9 in the brain remain largely unknown, particularly concerning its impact on brain pathology. To address this question, we conducted a comprehensive investigation of PCDH9 role in the male mouse hippocampus at the ultrastructural, biochemical, transcriptomic, electrophysiological and network level. We show that PCDH9 mainly localizes at glutamatergic synapses and its expression peaks in the first week after birth, a crucial time window for synaptogenesis. Strikingly, Pcdh9 KO neurons exhibit oversized presynaptic terminal and postsynaptic density (PSD) in the CA1. Synapse overgrowth is sustained by the widespread up-regulation of synaptic genes, as revealed by single-nucleus RNA-seq (snRNA-seq), and the dysregulation of key drivers of synapse morphogenesis, including the SHANK2/CORTACTIN pathway. At the functional level, these structural and transcriptional abnormalities result into increased excitatory postsynaptic currents (mEPSC) and reduced network activity in the CA1 of Pcdh9 KO mice. In conclusion, our work uncovers Pcdh9 pivotal role in shaping the morphology and function of CA1 excitatory synapses, thereby modulating glutamatergic transmission within hippocampal circuits.Significance statement Converging evidence indicates that genetic alterations in Protocadherin 9 (PCDH9) gene are associated with Autism Spectrum Disorder (ASD) and Major Depressive Disorder (MDD). However, our understanding of PCDH9 physiological role and molecular mechanisms in the brain, as well as its connection to synaptic dysfunction and brain pathology, remains limited. Here we demonstrate that Pcdh9 regulates the transcriptional profile, morphology and function of glutamatergic synapses in the CA1, thereby tuning hippocampal network activity. Our results elucidate the molecular and synaptic mechanisms of a gene implicated in neurodevelopmental and psychiatric disorders, and suggest potential hippocampal alterations contributing to the cognitive deficits associated with these conditions.

Flaxseed Oil: Safeguarding Neurological Health through Apoptosis and Oxidative Damage Defense

: The present study aims to investigate the neuroprotective properties of flaxseed oil (FSO) in reducing cadmium-induced neurotoxicity. The neuroprotective properties of FSO were observed in rats by examining the expression of caspase-3 and Bcl-2 to determine the antiapoptotic capabilities of FSO. Methods: Rats were given cadmium orally at a dosage of 5 mg/kg/day for 30 days, along with flaxseed oil (FSO) at doses of 2ml/kg/day and 3ml/kg/day for the same duration. The Morris watermaze test (MWM) and the Novel object recognition test (NOR) were performed to evaluate learning and memory abilities. We quantified the amounts of glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO), and acetylcholinesterase inhibitory activity (AChE) in the entire brain homogenate. Additionally, apoptosis and histopathology studies were conducted on rat brain tissues. Results: Intoxication with cadmium was associated with significant impairment of learning and memory in Morris watermaze (MWM) and novel object recognition (NOR) tests. The group that consumed Cd showed elevated levels of MDA, NO, and AChE in the brain homogenate, higher levels of caspase-3 and Bcl-2, and decreased levels of GSH compared to the control group. Animals treated with FSO exhibited improved learning and memory function, along with balanced levels of oxidative and cholinergic activity in brain tissue. Additionally, levels of caspase-3 and Bcl-2 were reduced in a similar way to the control group. Conclusions: The study demonstrates that flaxseed oil has positive effects by raising GSH and antiapoptotic potential levels while reducing MDA, NO, and AChE levels in the brain. This contributes to neuroprotection and decreases neuronal death, as supported by histopathological findings.

AMP-Activated Protein Kinase Treatment Ameliorates Chronic Restraint Stress Induced Memory Impairment in Early Adolescent Rat by Restoring Metabolite Profile and Synaptic Proteins

AMP-Activated Protein Kinase Treatment Ameliorates Chronic Restraint Stress Induced Memory Impairment in Early Adolescent Rat by Restoring Metabolite Profile and Synaptic Proteins

EFFICACY OF CANNABIDIOL (CBD) IN THE TREATMENT OF ALZHEIMER'S DISEASE: A CRITICAL REVIEW OF EVIDENCE AND CLINICAL IMPLICATIONS

Introduction: This study investigates the therapeutic potential of cannabidiol (CBD) in treating Alzheimer's disease (AD), which is characterized by progressive cognitive decline, memory impairment, and behavioral changes. As traditional treatment options are limited, the exploration of alternative therapies, including CBD, has gained prominence in recent years. Objective: The aim of this research is to evaluate the efficacy of CBD in modulating neuroinflammation and oxidative stress, as well as its potential impact on slowing the progression of Alzheimer's disease. Method: A literature review was conducted using ten articles published between 2019 and 2024. Databases such as the Virtual Health Library, LILACS Plus, and Medline were utilized, applying descriptors related to CBD and Alzheimer's disease. The articles were filtered based on specific inclusion criteria, focusing on studies published in Portuguese, Spanish, and English that are freely accessible online. Results: The reviewed literature indicates that CBD may inhibit the formation of beta-amyloid plaques, a hallmark of Alzheimer's pathology, suggesting its potential for both symptom relief and slowing disease progression. Additionally, the interaction between CBD and the endocannabinoid system (ECS) highlights its role in managing cognitive decline and memory issues associated with AD. Conclusion: While the findings are promising, there is a pressing need for more rigorous clinical studies to validate the efficacy and safety of CBD in Alzheimer's treatment. This research underscores the potential of cannabinoids as a therapeutic option in managing neurodegenerative diseases.

The Effect of Psilocybe cubensis on Spatial Memory and BDNF Expression in Male Rats Exposed to Chronic Unpredictable Mild Stress

ABSTRACT Psilocybin-containing mushrooms, commonly known as magic mushrooms, drastically affect mental processing, cognitive functioning, and the mood state. In the present study, we investigated the effect of the Psilocybe cubensis extract on spatial memory and the brain-derived neurotrophic factor (BDNF) in rats exposed to chronic unpredictable mild stress (CUMS). The duration of CUMS was 4 weeks. Spatial learning and memory were measured using the Morris water maze apparatus. The Psilocybe cubensis extract was intraperitoneally injected (20 mg/kg) in different time periods: 5 min before training, 24 h before training, 48 h before training, 5 min after training, and 5 min before the probe test. Results showed that CUMS impaired spatial learning and memory, and decreased BDNF in the hippocampus. Psilocybe cubensis (24 and 48 h before training) restored spatial learning, while (48 h before training) restored spatial memory impairment in CUMS rats. Psilocybe cubensis (24 and 48 h before training) increased BDNF in CUMS rats. Psilocybe cubensis administrations (expect 48 h before training) impaired spatial learning and memory and decreased BDNF levels in controls. In conclusion, we suggested that Psilocybe cubensis may be beneficial for the improvement of memory deficits induced by CUMS, while the time of injection seems to be an important factor in its final effect.

Molecular Roles of NADPH Oxidase-Mediated Oxidative Stress in Alzheimer's Disease: Isoform-Specific Contributions.

Oxidative stress is linked to the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder marked by memory impairment and cognitive decline. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau. AD is associated with an imbalance in redox states and excessive reactive oxygen species (ROS). Recent studies report that NADPH oxidase (NOX) enzymes are significant contributors to ROS generation in neurodegenerative diseases, including AD. NOX-derived ROS aggravates oxidative stress and neuroinflammation during AD. In this review, we provide the potential role of all NOX isoforms in AD pathogenesis and their respective structural involvement in AD progression, highlighting NOX enzymes as a strategic therapeutic target. A comprehensive understanding of NOX isoforms and their inhibitors could provide valuable insights into AD pathology and aid in the development of targeted treatments for AD.

Additive effect of clove essential oil combined with hydrogen inhalation improves psychological harm caused by lipopolysaccharide in mice

BackgroundPsychological anxiety and depression, as well as memory impairment, are frequently linked to inflammation. Clove essential oil (CEO) administration and hydrogen (H2) inhalation have been proven to have anti-inflammatory and alleviating effects on related psychological disorders in the past. The current study investigated the potential to improve anxiety-like behaviors and cognitive function by a combination of CEO and H2 treatment.MethodsThe mice were administered lipopolysaccharide (LPS) to induce inflammation and oxidative stress response and cause psychological disorders. Using this animal model, we conducted experiments to test whether essential oil and H2 inhalation could improve the psychological damage in behavior caused by LPS. Subsequently, elevated plus maze (EPM), forced swimming test (FST), and passive avoidance (PA) test were performed for evaluation of mice anxiety, depression, and response to electric shock, respectively. Furthermore, the biochemical analysis was used to examine the expression levels of inflammatory and oxidative stress markers.ResultsOur results showed that CEO administration and H2 inhalation alone or in combination positively improved inflammation-induced anxiety, depression, and cognitive memory deficits in the mice. In the single treatment groups, CEO demonstrated better results than H2 inhalation in the elevated plus maze, forced swimming, and passive avoidance tests, while combined treatment with both provided a further improved enhancement effect. Biochemical analysis of the cerebral cortex revealed that CEO and H2 therapy reversed the LPS-induced inflammation and oxidative stress response.ConclusionsOur results suggest that a combination of CEO and H2 has the potential to treat psychological disorders or neuropsychiatric disorders.

The Fundamental Neurobiological Mechanism of Oxidative Stress-Related 4E-BP2 Protein Deamidation.

Memory impairment is caused by the absence of the 4E-BP2 protein in the brain. This protein undergoes deamidation spontaneously in the neurons. 4E-BP2 deamidation significantly alters protein synthesis in the neurons and affects the balance of protein production required for a healthy nervous system. Any imbalance in protein production in the nervous system causes neurodegenerative diseases. Discovering what causes 4E-BP2 deamidation will make it possible to control this balance of protein production and develop effective treatments against neurodegenerative diseases such as Alzheimer's and Parkinson's. The purpose of this work is to discover the neurobiological mechanism that causes the deamidation reaction in the 4E-BP2 protein by performing immunoblotting in the retinal ganglia, the optic nerve, the dorsal root ganglia, the sciatic nerve, and the whole brain, extracted via dissection from 2-month-old, Wild-type male mice. The results show that axons and their unique properties cause neuron-specific 4E-BP2 deamidation in the nervous system, confirming conclusively that axons are the critical factors behind the fundamental neurobiological mechanism of 4E-BP2 protein deamidation.

Microglial depletion rescues spatial memory impairment caused by LPS administration in adult mice.

Recent studies have highlighted the importance of microglia, the resident macrophages in the brain, in regulating cognitive functions such as learning and memory in both healthy and diseased states. However, there are conflicting results and the underlying mechanisms are not fully understood. In this study, we examined the effect of depleting adult microglia on spatial learning and memory under both physiological conditions and lipopolysaccharide (LPS)-induced neuroinflammation. Our results revealed that microglial depletion by PLX5622 caused mild spatial memory impairment in mice under physiological conditions; however, it prevented memory deficits induced by systemic LPS insult. Inactivating microglia through minocycline administration replicated the protective effect of microglial depletion on LPS-induced memory impairment. Furthermore, our study showed that PLX5622 treatment suppressed LPS-induced neuroinflammation, microglial activation, and synaptic dysfunction. These results strengthen the evidence for the involvement of microglial immunoactivation in LPS-induced synaptic and cognitive malfunctions. They also suggest that targeting microglia may be a potential approach to treating neuroinflammation-associated cognitive dysfunction seen in neurodegenerative diseases.

Gene-dose-dependent reduction of Fshr expression improves spatial memory deficits in Alzheimer's mice.

High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of Alzheimer's disease (AD). We have shown recently that FSH directly activates the hippocampal FSH receptors (FSHRs) to drive AD-like pathology and memory loss in mice. To unequivocally establish a role for FSH in memory loss, we depleted the Fshr on a 3xTg background and utilized Morris Water Maze to study deficits in spatial memory. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5 months of age. The loss of memory acquisition and retrieval were both rescued in 3xTg;Fshr-/- mice and, to a lesser extent, in 3xTg;Fshr+/- mice-documenting clear gene-dose-dependent prevention of spatial memory loss. Furthermore, at 5 and 8 months, sham-operated 3xTg;Fshr-/- mice showed better memory performance during the learning and/or retrieval phases, further suggesting that Fshr deletion prevents age-related progression of memory deficits. This prevention was not seen when mice were ovariectomized, except in the 8-month-old 3xTg;Fshr-/- mice. There was also a gene-dose-dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial memory deficits in mice and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of memory loss in post-menopausal women.

Analysis and comparison of biomarkers for Alzheimer's disease

Abstract. Alzheimer's disease (AD), commonly known as dementia, is a neurodegenerative disease that causes memory and cognitive decline. Alzheimer's disease is a neurodegenerative disease that causes memory and cognitive deterioration in patients. 70% of the world's more than 50 million elderly patients suffer from Alzheimer's disease. Currently, scholars around the world mainly classify Alzheimer's disease (AD) patients into seven stages from onset to death. The pathogenesis of Alzheimer's disease (AD) has not yet been clarified by studies on different stages, and the main theories include the A- amyloid hypothesis and other theories such as abnormal phosphorylation of Tau protein. The A- amyloid hypothesis proposes that a type of A42 forms a large number of oligomers in the patient's brain due to misfolding and accumulation, which then develop into mature fibres and protofibrils, eventually accumulating into plaques that impede signalling between the patient's nerves and neurons to cause problems in the brain. The Tau protein theory proposes that it is due to over phosphorylation of pTau protein that disrupts the neuronal skeleton and forms neuronal fibre tangles (NFTS) causing impaired axonal transport to affect signalling. fibre tangles (NFTS) causing impaired axonal transport to affect signalling. This review provides an overview of the A amyloid hypothesis and the abnormal phosphorylation of Tau protein hypothesis, and compares their pathogenic mechanisms and proposes ideas to address the different mechanisms. This thesis finds that Alzheimer's disease (AD) can be treated using targeted approaches for different pathogenic mechanisms.

Intervention of age-related memory impairment by integrative musical stimuli

Abstract. Age-related memory impairment often causes significant distress for the elderly, imposing substantial burdens on families and society. It is widely known that auditory stimulation can trigger certain emotions and brain activities, but studies about factors that determine its effectiveness are lacking. This study aims to investigate the potential of music as an intervention for age-related memory impairment and the relative importance of music genre and preference level as factors that impact the effectiveness of music treatment. The research involves 22 participants and evaluates verbal episodic and working memory performance using the ten-word test (TWT) and digit span (DS) test, respectively. Additionally, electroencephalogram (EEG) data is analyzed to examine the impact of music on cortical electrical activity. This study involves the creation of a random forest machine learning model to predict long-term memory outcomes based on short-term data. Based on results comparing preference to music genre, we found that preference is a more important determining factor for the effectiveness of music treatment, and preference level one (most favourite music) treatment yielded the highest average improvements in both the TWT and the DS. Based on genre analysis, classical music stimuli were effective for improving long-term TWT and DS scores, and folk music stimuli effectively improved long-term TWT scores. Following folk music treatment, participants aged 65 and above yielded TWT score enhancements ranging from 25% to 66.7% and DS score enhancements ranging from 20% to 50%. This study also discovered the effectiveness of utilizing the random forest machine learning model to predict long-term TWT and DS outcomes based on short-term results, potentially enhancing the efficiency of future treatment.

Use of imidazo[1,5-a]quinoline scaffold as the pharmacophore in the design of bivalent ligands of central benzodiazepine receptors

The imidazo[1,5-a]quinoline scaffold of central benzodiazepine receptor (CBR) ligands was used as the pharmacophore in the design of bivalent ligands bearing spacers showing variable length and different physicochemical features. The newly designed compounds were synthesized along with the corresponding reference monovalent compounds bearing the corresponding spacers terminated with a tert-butoxycarbonyl group. The novel compounds were tested in binding assays with different CBR preparations such as the cerebral cortex from male CD-1 albino mice or the human recombinant α1β3γ2 and α2β3γ2 γ-aminobutyric acid type A receptors (GABAARs) stably expressed in mouse L(tk-) cells. The tested compounds showed IC50 values from the sub-micromolar up to the nanomolar range with very similar inhibition constants values for the two isoforms of GABAARs. The similarity in the affinity between the bivalent ligands and the corresponding monovalent ones appeared to rule out any bivalent interactions of these ligands with the two isoforms of GABAARs. Similarly, both series were able to inhibit the binding of radiolabeled flumazenil to GABAARs in cortical membranes of albino CD-1 mice, but most of the tested compounds showed biphasic inhibition curves, suggesting the existence of two well-distinct populations of binding sites. Finally, some CBR ligands selected from the bivalent ligands (i.e. 6a,c) and from the reference monovalent ligands (i.e. 7a) were then tested in vivo for their potential pharmacological effects, evaluating four classical benzodiazepine actions such as anticonvulsant, anxiolytic, locomotor, and anti-amnesic activities. All the tested compounds showed anticonvulsant and anxiolytic properties with neither muscle relaxant effect nor learning and memory impairments.

Acute Paraoxon-Induced Neurotoxicity in a Mouse Survival Model: Oxidative Stress, Dopaminergic System Alterations and Memory Deficits.

The secondary neurotoxicity induced by severe organophosphorus (OP) poisoning, including paraoxon (POX), is associated with cognitive impairments in survivors, who, despite receiving appropriate emergency treatments, may still experience lasting neurological deficits. Thus, the present study provides a survival mouse model of acute and severe POX poisoning to examine secondary neurotoxicity. Swiss CD-1 male mice were injected with POX (4 mg/kg, s.c.) followed by atropine (4 mg/kg, i.p.), pralidoxime (2-PAM; Pyridine-2-aldoxime methochloride) (25 mg/kg, i.p., twice, 1 h apart) and diazepam (5 mg/kg, i.p.), resulting in a survival rate >90% and Racine score of 5-6. Our results demonstrated that the model showed increased lipid peroxidation, downregulation of antioxidant enzymes and astrogliosis in the mouse hippocampus (HP) and prefrontal cortex (PFC), brain areas involved in cognitive functions. Moreover, dopamine (DA) levels were reduced in the hp, but increased in the PFC. Furthermore, the survival mouse model of acute POX intoxication did not exhibit phenotypic manifestations of depression, anxiety or motor incoordination. However, our results demonstrated long-term recognition memory impairments, which are in accordance with the molecular and neurochemical effects observed. In conclusion, this mouse model can aid in researching POX exposure's effects on memory and developing potential countermeasures against the secondary neurotoxicity induced by severe OP poisoning.

A novel phosphodiesterase 5 inhibitor, RF26, improves memory impairment and ameliorates tau aggregation and neuroinflammation in the P301S tauopathy mouse model of Alzheimer's disease

Phosphodiesterase-5 (PDE5) inhibitors are primarily used in the treatment of erectile dysfunction and pulmonary hypertension, but have also been reported to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD). This is likely to be through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling by elevating cGMP, a secondary messenger involved in processes of neuroplasticity. In the present study, we evaluated the efficacy of a novel PDE5 inhibitor, RF26, using P301S tauopathy mice model. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, including AD, Frontotemporal dementia (FTD), Supranuclear palsy and others. RF26 successfully targeted NO/cGMP signaling pathway and showed a significant improvement of spatial memory task performance of P301S mice using Morris Water Maze and T-maze. Furthermore, RF26 -treated mice showed a significant reduction of phosphorylated tau load, gliosis and downregulated pro-inflammatory cytokines. The presented data support the efficacy of RF26 as a potent PDE5 inhibitor and calls for further investigation as a potential therapeutic drug for Alzheimer's and other tauopathy related neurological disorders.