Memory Impairment Research Articles

Age, comorbid conditions, and cancer: Their associations with memory impairment in postmenopausal gynecologic cancer survivors in the Women's Health Initiative

Age, comorbid conditions, and cancer: Their associations with memory impairment in postmenopausal gynecologic cancer survivors in the Women's Health Initiative

Long-lasting pure topographical disorientation due to heading disorientation following left retrosplenial infarction: A report of two cases

Topographical disorientation is linked to lesions in the right hemisphere and typically resolves within a few months post-stroke. Persistent topographical disorientation is uncommon and frequently accompanied by impairments in visual memory, complicating the analysis of the underlying mechanisms. Herein, we report two cases of sustained pure topographical disorientation following cerebral hemorrhages in the left retrosplenial region. The patients exhibited disorientation in both familiar and unfamiliar settings, attributable to heading disorientation, a deficit in determining the directional relationship between one’s current position and a target location or external frames. The patients struggled with reconstructing large-scale spatial frameworks and integrating new egocentric and allocentric perspectives upon changes in body orientation. There were no landmark agnosia, egocentric disorientation, or anterograde disorientation. Although mild verbal memory deficits were observed, no other cognitive impairments, including visual memory deficits, were detected. Our findings imply that lesions confined to the left retrosplenial region can induce enduring heading disorientation and suggest a significant role for this area in processing and integrating spatial information necessary for large-scale navigation. Clarifying the features of topographical disorientation will significantly impact the therapeutic approaches, enhancing the quality of life for affected patients by restoring their independence and mobility.

Improvement of chlorpyrifos-induced cognitive impairment by mountain grape anthocyanins based on PI3K/Akt signaling pathway

The organophosphorus insecticide Chlorpyrifos (CPF) is widely used worldwide due to its high effectiveness. However, when ingested through the mouth and nose, it can cause severe neurotoxic effects and cognitive impairment. Natural anthocyanins show great potential in improving cognitive impairment. In this paper, we will delve into the protective effect of anthocyanins on CPF-induced cognitive impairment and its mechanism through the PI3K/Akt signaling pathway. Morris water maze, histopathological, ELISA and western blot analyses showed that anthocyanins effectively ameliorated CPF-induced spatial learning memory impairment in mice by ameliorating CPF-induced AChE inhibition, oxidative stress, and neuroinflammation and by modulating the levels of apoptosis (Caspase-3, Caspase-9) and autophagy (LC3II/ LC3I, Beclin1, p62, mTOR) biomarkers, in order to restore damaged hippocampal tissue morphology, neuron and synapse structures. To identify the action pathway of anthocyanins, we used KEGG and GO pathway enrichment analysis for screening prediction and western blot and molecular docking to verify that anthocyanins improve CPF-induced cognitive impairment by activating the PI3K/Akt pathway.

Neuroinflammatory Response and Redox-regulation Activity of Hyperoside in Manganese-induced Neurotoxicity Model of Wistar Rats.

Excessive manganese exposure can lead to neurotoxicity with detrimental effects on the brain. Neuroinflammatory responses and redox regulation play pivotal roles in this process. Exploring the impact of hyperoside in a Wistar rat model offers insights into potential neuroprotective strategies against manganese-induced neurotoxicity. The study investigated the neuroprotective efficacy of hyperoside isolated from the ethanol leaf extract of Gongronema latifolium (HELEGL), in the brain tissue of Wistar rats following 15 consecutive days of exposure to 30 mg/L of MnCl2. Control animals in Group 1 had access to regular drinking water, while animals in groups 2-4 were exposed to MnCl2 in their drinking water. Groups 3 and 4 also received additional HELEGL at doses of 100 mg/kg and 200 mg/kg of body weight, respectively. In Group 5, HELEGL at a dose of 100 mg/kg of body weight was administered alone. Treatment with HELEGL commenced on day 8 via oral administration. HELEGL effectively mitigated MnCl2-induced memory impairment, organ-body weight discrepancies, and fluid intake deficits. Exposure to MnCl2 increased the activities or levels of various markers such as acyl peptide hydrolase, tumour necrosis factor-α, dipeptidyl peptidase IV, nitric oxide, IL-1β, prolyl oligopeptidase, caspase-3, myeloperoxidase, H2O2, and malondialdehyde, while it decreased the activities or levels of others, including AChE, BChE, DOPA, serotonin, epinephrine, norepinephrine, GST, GPx, CAT, SOD, GSH, and T-SH (p < 0.05). In contrast, HELEGL effectively counteracted the adverse effects of MnCl2 by alleviating oxidative stress, inflammation, apoptosis, mitochondrial dysfunction, cognitive deficits, and bolstering the antioxidant status. Moreover, HELEGL restored the normal histoarchitecture of the brain, which had been distorted by MnCl2. In summary, HELEGL reversed the causative factors of neurodegenerative diseases induced by MnCl2 exposure, suggesting its potential for further exploration as a prospective therapeutic agent in the management of Alzheimer's disease and related forms of dementia.

Neuronal connectivity, behavioral, and transcriptional alterations associated with the loss of MARK2.

Neuronal connectivity is essential for adaptive brain responses and can be modulated by dendritic spine plasticity and the intrinsic excitability of individual neurons. Dysregulation of these processes can lead to aberrant neuronal activity, which has been associated with numerous neurological disorders including autism, epilepsy, and Alzheimer's disease. Nonetheless, the molecular mechanisms underlying abnormal neuronal connectivity remain unclear. We previously found that the serine/threonine kinase Microtubule Affinity Regulating Kinase 2 (MARK2), also known as Partitioning Defective 1b (Par1b), is important for the formation of dendritic spines invitro. However, despite its genetic association with several neurological disorders, the invivo impact of MARK2 on neuronal connectivity and cognitive functions remains unclear. Here, we demonstrate that the loss of MARK2 invivo results in changes to dendritic spine morphology, which in turn leads to a decrease in excitatory synaptic transmission. Additionally, the loss of MARK2 produces substantial impairments in learning and memory, reduced anxiety, and defective social behavior. Notably, MARK2 deficiency results in heightened seizure susceptibility. Consistent with this observation, electrophysiological analysis of hippocampal slices indicates underlying neuronal hyperexcitability in MARK2-deficient neurons. Finally, RNAseq analysis reveals transcriptional changes in genes regulating synaptic transmission and ion homeostasis. These results underscore the invivo role of MARK2 in governing synaptic connectivity, neuronal excitability, and cognitive functions.

Preoperative subjective impairments in language and memory in brain tumor patients

BackgroundSubjective reports can reveal relevant information regarding the nature of the impairment of brain tumor patients, unveiling potential gaps in current assessment practices. The co-occurrence of language and memory impairments has been previously reported, albeit scarcely. The aim of this study is therefore to understand the co-occurrence of subjective language and memory complaints in the preoperative state of brain tumor patients and its impact on Quality of Life (QoL).Methods31 brain tumor patients (12 LGG, 19 HGG) underwent a semi-structured interview to assess subjective complaints of language deficits, co-occurrences between language and memory dysfunction, and changes in QoL. Group and subgroup analyses were conducted to provide general and tumor grade specific data.Results48.4% of patients mentioned co-occurrence of language and memory impairments in reading, writing, and conversation. The HGG group reported co-occurrences in all three of these (reading: 31.6%; writing: 21.1%; conversation: 26.3%), while the LGG only described co-occurrences in reading (25%) and conversation (8.3%), although these were not statistically significant. All patients with co-occurring language and memory deficits reported these to be linked to reduced QoL (48.4%). In patients with an HGG, this number was slightly higher (52.6%) than in patients with an LGG (41.7%).ConclusionLanguage impairments co-occur with memory dysfunction as perceived in patients’ daily life. Patients see these impairments as affecting their quality of life. Further attention to dedicated language and memory tasks seems necessary.

Application of Multi-Input Multi-Output Brain-Computer Interface in Cognitive Assessment for Alzheimer’s Disease

This research aims to augment human cognitive abilities, particularly memory function, through the development of innovative prosthetics. The hippocampus, a crucial brain region involved in memory encoding and recall, has been the focal point of numerous studies seeking to develop prosthetics that can restore or enhance memory function in individuals with impairments such as Alzheimer’s disease. This review examines two studies that delve into the development and application of hippocampal neural prosthetics, highlighting the potential of these prosthetics to revolutionize the treatment of memory impairments. One study utilized static neural stimulation patterns to enhance memory for specific information content, while another developed a nonlinear Multiple Input Multiple Output (MIMO) dynamic model to predict and stimulate neural activity patterns during memory encoding. Both studies demonstrated significant improvements in memory performance. Additionally, this paper discusses the clinical significance and application prospects of hippocampal neural prosthetics, including the potential for implantable prosthetics and the widespread applicability of MIMO stimulation. Furthermore, the paper explores advanced modeling and classification techniques for neural ensembles and visual memory decoding, including Volterra-type hierarchical modeling, optimal multi-unit stimulation patterns, and a sparse classification model for decoding visual memories. Finally, the paper presents the implementation and evaluation of neural prosthesis systems, including an application-specific integrated circuit (ASIC) design for a hippocampal prosthesis and a high-performance, scalable system architecture for real-time estimation of neural activity. These advancements hold promise for future research and applications in neural prosthetics for memory enhancement.

Memory impairment after one year of the acute episode of Covid-19 infection

Abstract Introduction Memory impairment is one of the most frequently reported sequelae of COVID-19 infection. The aim of our study was to estimate the risk of memory disorders one year after the acute episode of COVID-19 infection in the Tunisian population of Monastir. Methods This is a cohort study conducted in Monastir University Hospital. The study included two groups: Exposed subjects were randomly selected among those with a positive diagnosis of COVID-19 between September 2021 and January 2022. The non exposed group was selectd among subjects with a negative COVID-19 diagnosis during the same period and who had no COVID infection during the following year. The Mac Nair scale was used to assess memory impairment after one year of follow up. Results Our study included 140 subjects diagnosed with Covid-19 and 139 subjects who had never been in contact with this virus. The incidence rate of memory impairment at one year post-Covid-19 infection was 17.9% (IC95% [11.5 - 24.2%]), whereas in the non exposed group it was 9.4% (IC95% [4.45% -14.5%]). Multivariate analysis revealed that the group exposed to Covid-19 had a significantly higher Mac-Nair Total score after one year of the acute episode of infection compared with the non exposed group (exp β = 1.25, IC95% [1.10; 1.42]). The other main predictors of memory impairment in the study population were age (exp β = 1.006, IC95% [1.001; 1.01]), diabetes (exp β = 1.67, IC95% [1.44; 1.95]), history of anxiety and depression ((exp β = 1.71, IC95% [1.35; 2.17]) and obesity (exp β = 1.25, IC95% [1.10; 1.42]), whereas vaccination with two or more doses prior to COVID-19 infection (exp β = 0.84, IC95% [0.74; 0.96]) and male gender (exp β = 0.65, IC95% [ 0.57; 0.73]) were found to be protective against these disorders. Conclusions Our study allowed us to estimate the risk of long-term memory disorders following Covid-19 infection. This could help better guide preventive measures to reduce the incidence of these disorders. Key messages • The incidence rate of memory impairment at one year post-Covid-19 infection was 17.9%. • The main other predictors of memory impairment were age, female gender, diabetes, history of anxiety and depression and obesity whereas vaccination prior to COVID-19 infection was a protective factor.

High Behavioral Reactivity to Novelty as a Susceptibility Factor for Memory and Anxiety Disorders in Streptozotocin-Induced Neuroinflammation as a Rat Model of Alzheimer’s Disease

Individual differences in responsiveness to environmental factors, including stress reactivity and anxiety levels, which differ between high (HR) and low (LR) responders to novelty, might be risk factors for development of memory and anxiety disorders in sporadic Alzheimer’s disease (sAD). In the present study, we investigated whether behavioral characteristics of the HR and LR rats, influence the progression of sAD (neuroinflammation, β-amyloid peptide, behavioral activity related to memory (Morris water maze) and anxiety (elevated plus maze, white and illuminated open field test) in streptozotocin (STZ)-induced neuroinflammation as a model of early pathophysiological alterations in sAD. Early (45 days) in disease progression, there was a more severe impairment of reference memory and higher levels of anxiety in HRs compared with LRs. Behavioral depression in HRs was associated with higher expression of β-amyloid deposits, particularly in the NAcS, and activation of microglia (CD68+ cells) in the hypothalamus, as opposed to less inflammation in the hippocampus, particularly in CA1, compared with LRs in late (90 days) sAD progression. Our findings suggest that rats with higher behavioral activity and increased responsivity to stressors show more rapid progression of disease and anxiety disorders compared with low responders to novelty in the STZ-induced sAD model.

The collaborative cross mouse for studying the effect of host genetic background on memory impairments due to obesity and diabetes.

Over the past few decades, a threefold increase in obesity and type 2 diabetes (T2D) has placed a heavy burden on the health-care system and society. Previous studies have shown correlations between obesity, T2D, and neurodegenerative diseases, including dementia. It is imperative to further understand the relationship between obesity, T2D, and cognitive deficits. This investigation tested and evaluated the cognitive impact of obesity and T2D induced by high-fat diet (HFD) and the effect of the host genetic background on the severity of cognitive decline caused by obesity and T2D in collaborative cross (CC) mice. The CC mice are a genetically diverse panel derived from eight inbred strains. Our findings demonstrated significant variations in the recorded phenotypes across different CC lines compared to the reference mouse line, C57BL/6J. CC037 line exhibited a substantial increase in body weight on HFD, whereas line CC005 exhibited differing responses based on sex. Glucose tolerance tests revealed significant variations, with some lines like CC005 showing a marked increase in area under the curve (AUC) values on HFD. Organ weights, including brain, spleen, liver, and kidney, varied significantly among the lines and sexes in response to HFD. Behavioral tests using the Morris water maze indicated that cognitive performance was differentially affected by diet and genetic background. Our study establishes a foundation for future quantitative trait loci mapping using CC lines and identifying genes underlying the comorbidity of Alzheimer's disease (AD), caused by obesity and T2D. The genetic components may offer new tools for early prediction and prevention.

Motor, mood, and memory impairments persist during remission periods in chronic colitis and are influenced by neuroinflammation and sex.

Ulcerative colitis is a chronic pathology characterized by relapsing-remitting phases of intestinal inflammation. Additionally, some patients develop neuropsychiatric disorders, such as depression and anxiety, or cognitive deficits. We aimed to investigate whether the development of chronic colitis elicits memory, locomotion, and mood impairments. It further examined whether these impairments are influenced by the relapsing-remitting phases of the colitis or by sex. Here, we used a chronic colitis model in male and female rats, induced with sodium dextran sulfate, mirroring the phases of human ulcerative colitis. Our results revealed that the severity of colitis was slightly higher in males than females. Chronic colitis triggered motor and short-term memory deficits and induced anxiety- and depression-like behaviors that remained throughout the development of the disease. There are also sex differences under control or inflammatory conditions. Therefore, in both situations, females compared to males displayed: (i) slightly lower locomotion, (ii) increased anxiety-like behaviors, (iii) similar depression-like behaviors, and (iv) similar short-term memory deficit. Additionally, under control conditions, the mRNA levels of IL-1β, IL-6, and TNF-α were higher in the female hippocampus. In both sexes, when chronic colitis was established, the neuroinflammation was evidenced by increased mRNA levels of these three cytokines in the hippocampus and in the motor and prefrontal cortices. Interestingly, this neuroinflammation was slightly greater in males. In summary, we show that the development of chronic colitis caused persistent behavioral abnormalities, highlighting sex differences, and that could be a consequence, at least in part, of the increase in IL-1β, IL-6, and TNF-α in the brain.

Memory complaints after COVID-19: a potential indicator of primary cognitive impairment or a correlate of psychiatric symptoms?

Cognitive impairment and symptoms of psychiatric disorders have been reported frequently as features of post-acute sequelae of SARS-CoV-2 infection. This study aims to investigate subjective memory complaints in COVID-19 survivors and determine if these are more strongly associated with objective cognitive impairment related to sequelae of SARS-CoV-2 infection or with symptoms of psychiatric conditions. A total of 608 COVID-19 survivors were evaluated in-person 6–11 months after hospitalization, with 377 patients assigned to a “no subjective memory complaint (SMC)” group and 231 patients assigned to an SMC group based on their Memory Complaint Scale scores. Follow-up evaluations included an objective cognitive battery and scale-based assessments of anxiety, depression, and post-traumatic stress symptoms. We found the perception of memory impairment in COVID-19 survivors to be more strongly associated to core symptoms of psychiatric conditions rather than to primary objective cognitive impairment. Univariate analysis indicated significant differences between the “no SMC” and SMC groups, both for the psychiatric symptom evaluations and for the cognitive evaluations (p < 0.05); however, the psychiatric symptoms all had large partial eta-squared values (ranging from 0.181 to 0.213), whereas the cognitive variables had small/medium partial eta-squared values (ranging from 0.002 to 0.024). Additionally, multiple regression analysis indicated that only female sex and depressive and post-traumatic stress symptoms were predictors of subjective memory complaints. These findings may help guide clinical evaluations for COVID-19 survivors presenting with memory complaints while also serving to expand our growing understanding of the relationship between COVID-19, subjective memory complaints, and the risk of cognitive decline.

Emerging many-to-one weighted mapping in hippocampus-amygdala network underlies memory formation

Memories are crucial for daily life, yet the network-level organizing principles governing neural representations of experiences remain unknown. Employing dual-site in vivo recording in freely behaving male mice, here we show that hippocampal dorsal CA1 (dCA1) and basolateral amygdala (BLA) utilize distinct coding strategies for novel experiences. A small assembly of BLA neurons emerged active during memory acquisition and persisted through consolidation, whereas most dCA1 neurons were engaged in both processes. Machine learning decoding revealed that dCA1 population spikes predicted BLA assembly firing rate, suggesting that most dCA1 neurons concurrently index an episodic event by rapidly establishing weighted communication with a specific BLA assembly – a process we term “many-to-one weighted mapping.” We also found that dCA1 reactivations preceded BLA assembly activity preferably during elongated and enlarged dCA1 ripples. Using a closed-loop strategy, we demonstrated that suppressing BLA activity after large dCA1 ripples impaired memory. These findings highlight a many-to-one weighted mapping mechanism underlying both the acquisition and consolidation of new memories.

Why does invasive brain stimulation sometimes improve memory and sometimes impair it?

Invasive brain stimulation is used to treat individuals with episodic memory loss; however, studies to date report both enhancement and impairment of memory. This Essay discusses the sources of this variability, and suggests a path towards developing customized stimulation protocols for more consistent memory enhancement.

Acute Administration of Edaravone Improves Cognitive Impairment in a Mouse Model of mPFC Ischemia: Crosstalk Between Necroptosis, Neuroinflammation, and Antioxidant Defense.

Edaravone (Eda), a well-known free radical scavenger, has been reported as a possible therapeutic agent for ischemic stroke patients' recovery. This study aimed to investigate the effects of time-dependent treatment with Eda on medial prefrontal cortex (mPFC) ischemia. Mice were randomly allocated into six groups: control, sham, normal saline, Eda-I, Eda-II, and Eda-III. After induction of a photothrombotic ischemia in the mPFC region, Eda-I, Eda-II, and Eda-III groups received 3mg/kg Eda intraperitoneally at the times of 0, 2, and 6h post-surgery. After 1day of recovery, the mice underwent behavioral tests (open field, novel object recognition, and T-maze). Next, necroptosis, NOD-like receptor protein 3 (NLRP3), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related protein levels were measured in the lesioned area using western blot analysis. For double confirmation, IL-1β and IL-18 were also assessed by immunofluorescence in the area. Further, histological evaluations were performed to measure tissue damage. The results showed that mPFC ischemia impaired recognition and spatial working memory without affecting locomotor activity, while immediate Eda administration improved cognitive impairments. Furthermore, acute Eda treatment reduced RIP1, RIP3, and MLKL levels, inhibited NLRP3 inflammasome proteins (NLRP3, ASC, and Cas1), decreased IL-1β and IL-18, upregulated Nrf2 and its targets (NQO-1 and HO-1), and diminished tissue damage. Our results highlighted the effects of acute administration of Eda post-stroke on improving cognitive impairments by suppressing necroptosis and NLRP3 inflammasome pathways and activating the Nrf2 antioxidant defense mechanism.

Specific and Polyfunctional T Cell Response Against N-Methyl-d-aspartate Receptor in an Autoantibody-Mediated Encephalitis Model

Background: Anti-N-Methyl-d-aspartate receptor (NMDAR) autoimmune encephalitis (NMDAR AE) is an autoimmune disease characterized by severe psychiatric and neurological symptoms. While the pathogenic role of antibodies (Abs) directed against the GluN1 subunit of NMDAR is well described in this disease, the immune mechanisms involved in the generation of the autoimmune B cell response, especially the role of T helper cells, are poorly understood. Previously, we developed a B-cell-mediated mouse model of NMDAR AE by immunization with a GluN1359–378 peptide that drives a series of symptoms that recapitulate AE such as anxiety behaviour and spatial memory impairment. Results: In this mouse model, we identified anti-GluN1-specific CD4+ but also CD8+ T cells in both spleen and meninges. T helper cells have a polyfunctional profile, arguing for a T and B cell crosstalk to generate anti-GluN1 pathogenic Abs. Interestingly, proteomic analysis of AE meninges showed enrichment of differentially expressed proteins in biological processes associated with B cell activation and cytokine signalling pathways. Conclusions: This study identified, for the first time, a potential contribution of T helper cells in the pathology of NMDAR AE and paved the way for the development of future tolerogenic approaches to treat relapses.

Safflower Yellow Alleviates Cognitive Impairment in Mice by Modulating Cholinergic System Function, Oxidative Stress, and CREB/BDNF/TrkB Signaling Pathway

Ethnopharmacological relevanceCarthamus tinctorius L. (Safflower) was believed to have multiple benefits, including antioxidant effects, enhanced learning and memory, and improving neuronal injury. Safflower Yellow(SY) are the main active ingredients of Safflower, displays strong pharmacological potential treatment of Alzheimer's disease(AD). However, its effect on memory impairments remains insufficiently investigated. Aim of the study:The study aims to investigate the effects of SY on cognitive functions in memory impairments model and to explore the mechanism of its action. Materials and methodsWe utilized the Morris Water Maze, Step-Through Test, Step-Down Test to assess the potential of SY in ameliorating learning and memory dysfunction caused by SCOP, NaNO2 and ethanol in mice. Bioinformatic analysis and molecular biological approaches were used to study the related mechanisms of SY on anti-memory impairments. ResultsThe results of the Morris Water Test suggested that SY could shorten the escape latency and the time of the first crossing platform in the mice with memory acquisition and memory consolidation impairments, and increase the platform crossing times. The results of the Step-Though test and Step-Down test showed that the escape latency in the mice was prolonged and the number of errors was reduced after SY treatment. ELISA experiments indicated that SY decreased the AChE activities, increased the ChAT activities, and modulated oxidative stress markers (SOD, MDA, and GSH-PX) in scopolamine-induced mice. Western Blot and Nissl staining showed that SY could activated BDNF/TrkB/CREB signaling pathway and reduced neuronal damage. ConclusionThe findings present that SY can restore the function of the cholinergic system, inhibit oxidative stress, regulate the expression of upstream and downstream proteins in the CREB/BDNF/TrkB pathway, and alleviate brain tissue damage to improve memory impairment in mice.

Metformin Mitigates Trimethyltin-Induced Cognition Impairment and Hippocampal Neurodegeneration

The neurotoxicant trimethyltin (TMT) triggers cognitive impairment and hippocampal neurodegeneration. TMT is a useful research tool for the study of Alzheimer's disease (AD) pathogenesis and treatment. Although the antidiabetic agent metformin has shown promising neuroprotective effects, however, its precise modes of action in neurodegenerative disorders need to be further elucidated. In this study, we investigated whether metformin can mitigate TMT cognition impairment and hippocampal neurodegeneration. To induce an AD-like phenotype, TMT was injected i.p. (8 mg/kg) and metformin was administered daily p.o. for 3 weeks at 200 mg/kg. Our results showed that metformin administration to the TMT group mitigated learning and memory impairment in Barnes maze, novel object recognition (NOR) task, and Y maze, attenuated hippocampal oxidative, inflammatory, and cell death/pyroptotic factors, and also reversed neurodegeneration-related proteins such as presenilin 1 and p-Tau. Hippocampal level of AMP-activated protein kinase (AMPK) as a key regulator of energy homeostasis was also improved following metformin treatment. Additionally, metformin reduced hippocampal acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP)-positive reactivity, and prevented the loss of CA1 pyramidal neurons. This study showed that metformin mitigated TMT-induced neurodegeneration and this may pave the way to develop new therapeutics to combat against cognitive deficits under neurotoxic conditions.

Crocin has a greater therapeutic role in the restoration of behavioral impairments caused by maternal social isolation in adolescent than in adult offspring probably through GSK-3beta downregulation

Parental stress drastically impairs cognitive and behavioral functions of the offspring. Social isolation, as one of the most stressful conditions for social animals including rats induces a wide range of destructive effects on behavioral functions. On the other hand, Crocin (active component of Crocus sativa) induces pro-cognitive and neuroprotective effects. In the present study, we aimed to investigate the effects of prolonged maternal social isolation (pre-gestational) and crocin treatment on cognitive and behavioral functions in both adolescent and adult offspring. Female adult rats (mothers) were socially isolated from PND 30 to PND 80 (50 days). The treatment was performed by intraperitoneal injections of crocin (10, 30, and 50 mg/kg) during PND 39–45 or PND 59–65 (7 consecutive days), in the rat offspring. Behavioral assessments were done when the offspring were on PND 45 (adolescent) or PND 65 (adult). The expression level of Glycogen synthase kinase-3 beta (GSK-3beta) in the hippocampus was measured using real-time PCR. The results showed maternal social isolation decreased locomotion and impaired memory in adolescents, and increased anxiety- and depressive-like behaviors and GSK-3beta level, and decreased pain threshold in both adolescents and adults. Crocin (30 and 50 mg/kg) restored or attenuated the effect of maternal social isolation on behavioral functions and GSK-3beta in adolescents and adults, with more effect in adolescents. In conclusion, we showed that crocin treatment can restore the destructive effects of maternal social isolation stress in the offspring, with stronger therapeutic effects in adolescents. Also, GSK-3beta downregulation may underlie the beneficial effects of crocin.

Brivaracetam and rufinamide combination increased seizure threshold and improved neurobehavioral deficits in corneal kindling model of epilepsy.

Besides seizures, a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy, which further debilitates their quality of life. This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses, respectively, on corneal kindling-induced generalized seizures and behavioral alterations. Furthermore, observed convulsive frequency and behavioral changes were correlated to post-kindling-induced changes in the activity of markers of oxidative stress. Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz electrical stimulations (3 mA) for 3 s for 12 days until animals reached a fully kindled state. After the kindling procedure, animals were tested using a set of behavioral tests, and neurochemical alterations were assessed. Corneal-kindled animals exhibited intense generalized convulsions, altered behavioral phenotypes typified by positive symptoms (hyperlocomotion), negative symptoms (anxiety and anhedonia), and deficits in semantic and working memory. BRV 10 + RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4-5 seizures and improved phenotypical deficits, that is, anxiety, depression, and memory impairments. Moreover, this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult. Based on our outcomes, this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.