Crocin attenuates the lipopolysaccharide-induced neuroinflammation via expression of AIM2 and NLRP1 inflammasome in an experimental model of Parkinson's disease.

The underlying mechanisms of inflammasome activation and the following dopaminergic neuron loss caused by chronic neuroinflammation remain entirely unclear. Therefore, this study aimed to investigate the impact of crocin on the inflammasome complex within an experimental model of Parkinson's disease (PD) using male Wistar rats. PD was induced by the stereotaxic injection of lipopolysaccharide (LPS), and crocin was intraperitoneally administrated one week before the lesion, and then treatment continued for 21 days. Open field (OF) and elevated plus maze tests were applied for behavioral assays. Furthermore, hematoxylin and eosin (H&E) and immunostaining were performed on whole brain tissue, while dissected substantia nigra (SN) was used for immunoblotting and real-time PCR to evaluate compartments involved in PD. The time spent in the center of test was diminished in the LPS group, while treatment with 30 mg/kg of crocin significantly increased it. H&E staining showed a significant increase in cell infiltration at the site of LPS injection, which was ameliorated upon crocin treatment. Notably, crocin-treated animals showed a reduced number of caspase-1 and IL-1ß positive cells, whereas the number of positive cells was increased in the LPS group (P < 0.05). A significant decrease in tyrosine hydroxylase (TH) expression was also found in the LPS group, while crocin treatment significantly elevated its expression. IL-1ß, IL-18, NLRP1, and AIM2 genes expression significantly increased in the LPS group. On the other hand, treatment with 30 mg/kg of crocin significantly downregulated the expression levels of these genes along with NLRP1 (P < 0.05). In summary, our findings suggest that crocin reduces neuroinflammation in PD by diminishing IL-1ß and caspase-1 levels, potentially by inhibiting the expression of AIM2 and NLRP1 genes.

The role of Toll-like receptors in neuropsychiatric disorders: Immunopathology, treatment, and management.

Neuropsychiatric disorders denote a broad range of illnesses involving neurology and psychiatry. These disorders include depressive disorders, anxiety, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, autism spectrum disorders, headaches, and epilepsy. In addition to their main neuropathology that lies in the central nervous system (CNS), lately, studies have highlighted the role of immunity and neuroinflammation in neuropsychiatric disorders. Toll-like receptors (TLRs) are innate receptors that act as a bridge between the innate and adaptive immune systems via adaptor proteins (e.g., MYD88) and downstream elements; TLRs are classified into 13 families that are involved in normal function and illnesses of the CNS. TLRs expression affects the course of neuropsychiatric disorders, and is influenced during their pharmacotherapy; For example, the expression of multiple TLRs is normalized during the major depressive disorder pharmacotherapy. Here, the role of TLRs in neuroimmunology, treatment, and management of neuropsychiatric disorders is discussed. We recommend longitudinal studies to comparatively assess the cell-type-specific expression of TLRs during treatment, illness progression, and remission. Also, further research should explore molecular insights into TLRs regulation and related pathways.

Mortality in ICU COVID-19 Patients Is Associated with Neutrophil-to-Lymphocyte Ratio (NLR): Utility of NLR as a Promising Immunohematological Marker.

Background: Achieving a suitable medical laboratory index is very important for the prediction of clinical outcome of COVID-19 patients hospitalized to the intensive care unit (ICU). The correlation between neutrophil-to-lymphocyte ratio (NLR) and unfavorable outcome of COVID-19 patients hospitalized to ICU was the aim of this study. Methods: We evaluated a cross-sectional study of 312 COVID-19 patients who were hospitalized to the ICU (confirmed by PCR and CT-Scan), in Babol city, Mazandaran province. WBC, RBC, lymphocyte, neutrophil, monocyte, platelet count, NLR, C-reactive protein (CRP), ESR, MCV, MHC, and other factors were evaluated. Results: Our findings indicated that all patients aged 56 to 69 years with COVID-19 had a significant difference (P < 0.05) in neu, lymph, PLT count, NLR, ESR, Hb, and CRP. Also, NLR was significantly (P < 0.05) correlated with the death or discharge of the ICU hospitalized patients. The cut-off of NLR was 7.02 and the mean of NLR was 11.3 ± 10.93 and 5.8 ± 7.45 in death and discharge COVID-19 patients hospitalized to ICU, respectively. ROC curve indicated that, for NLR, the area under curve was 0.76. Conclusions: Our findings showed that NLR can be utilized as a clinical laboratory predictive parameter for mortality of COVID-19 patients admitted to ICU.

Surgical tool entrapment in a young patient with recurrent lumbar spinal stenosis: a case report.

Lumbar spinal stenosis (LSS) is a prevalent cause of leg and back pain. In the youth, LSS is not common and mainly results from hereditary musculoskeletal disorders. Moreover, spinal fusion is a surgical approach to the treatment of LSS. Entrapment of surgical tools due to breakage is a rare yet important phenomenon in such operations. Therefore, neurological sequelae of these events need to be explored. The case was a 24-year-old male complaining of local back pain. Initially, he was diagnosed with LSS at L4 and L5. After the fusion of the vertebrae by the posterior spinal fusion (PSF) method, the patient's pain was resolved. However, the subject complained of worsening local back pain limiting his ability to do routine tasks. A few years later, radiographical evaluations indicated the possible presence of a surgical tool that could not be removed via surgery. During a third operation, the object was removed, and the patient's symptoms recovered. Immediate removal of entrapped surgical objects is necessary due to risks associated with migration and central nervous system damage. Comparing our results to other similar reports, we conclude that in cases of foreign object entrapment, neurological sequelae may be nonexistent or progressively worsen. Also, sequelae emerge either soon after the operation or emerge later. This complicates the diagnosis of such events and the decision of whether to subject the patient to additional neurosurgical operations to remove the tool. These variations may be observed due to the moving of the entrapped tool. Follow-up of neurological sequelae in spinal surgery patients is recommended.

Empagliflozin treatment of cardiotoxicity: A comprehensive review of clinical, immunobiological, neuroimmune, and therapeutic implications.

Cancer and cardiovascular disorders are known as the two main leading causes of mortality worldwide. Cardiotoxicity is a critical and common adverse effect of cancer-related chemotherapy. Chemotherapy-induced cardiotoxicity has been associated with various cancer treatments, such as anthracyclines, immune checkpoint inhibitors, and kinase inhibitors. Different methods have been reported for the management of chemotherapy-induced cardiotoxicity. In this regard, sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of antidiabetic agents, have recently been applied to manage heart failure patients. Further, SGLT2i drugs such as EMPA exert protective cardiac and systemic effects. Moreover, it can reduce inflammation through the mediation of major inflammatory components, such as Nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasomes, Adenosine 5'-monophosphate-activated protein kinase (AMPK), and c-Jun N-terminal kinase (JNK) pathways, Signal transducer and activator of transcription (STAT), and overall decreasing transcription of proinflammatory cytokines. The clinical outcome of EMPA administration is related to improving cardiovascular risk factors, including body weight, lipid profile, blood pressure, and arterial stiffness. Intriguingly, SGLT2 suppressors can regulate microglia-driven hyperinflammation affecting neurological and cardiovascular disorders. In this review, we discuss the protective effects of EMPA in chemotherapy-induced cardiotoxicity from molecular, immunological, and neuroimmunological aspects to preclinical and clinical outcomes.

Is neuropilin-1 the neuroimmune initiator of multi-system hyperinflammation in COVID-19?

A major immunopathological feature of Coronavirus disease-2019 (COVID-19) is excessive inflammation in the form of "cytokine storm". The storm is characterized by injurious levels of cytokines which form a complicated network damaging different organs, including the lungs and the brain. The main starter of "cytokine network" hyperactivation in COVID-19 has not been discovered yet. Neuropilins (NRPs) are transmembrane proteins that act as neuronal guidance and angiogenesis modulators. The crucial function of NRPs in forming the nervous and vascular systems has been well-studied. NRP1 and NRP2 are the two identified homologs of NRP. NRP1 has been shown as a viral entry pathway for SARS-CoV2, which facilitates neuroinvasion by the virus within the central or peripheral nervous systems. These molecules directly interact with various COVID-19-related molecules, such as specific regions of the spike protein (major immune element of SARS-CoV2), vascular endothelial growth factor (VEGF) receptors, VEGFR1/2, and ANGPTL4 (regulator of vessel permeability and integrity). NRPs mainly play a role in hyperinflammatory injury of the CNS and lungs, and also the liver, kidney, pancreas, and heart in COVID-19 patients. New findings have suggested NRPs good candidates for pharmacotherapy of COVID-19. However, therapeutic targeting of NRP1 in COVID-19 is still in the preclinical phase. This review presents the implications of NRP1 in multi-organ inflammation-induced injury by SARS-CoV2 and provides insights for NRP1-targeting treatments for COVID-19 patients.

Neurological adverse effects of chimeric antigen receptor T-cell therapy.

INTRODUCTION: Chimeric antigen receptor (CAR) T-cell is among the most prevalent approaches that act by directing T-cells toward cancer; however, they need to be optimized to minimize side effects and maximize efficacy before being used as standard treatment for malignancies. Neurotoxicity associated with CAR T-cell therapy has been well-documented in recent works. AREAS COVERED: In this regard, two established syndromes exist. Immune effector cell-associated neurotoxicity syndrome (ICANS), previously called cytokine release encephalopathy syndrome (CRES), is a neuropsychiatric condition which can occur after therapy by immune effector cells (IEC) and T-lymphocytes utilizing treatments. Another syndrome is cytokine release syndrome (CRS), which may overlap with ICANS. EXPERT OPINION: ICANS clinical manifestations include cerebral edema, mild lethargy, aphasia, and seizures. Notably, ICANS is associated with changes to EEG and neuroradiological findings. Therefore, it is necessary to make a timely and accurate diagnosis of neurological complications of CAR T-cells by clinical presentations, neuroimaging, and EEG. Since neurological events by different CAR T-cell products are heterogeneous, guides should be developed according to each product. Here, we provide an updated review of general information on CAR T-cell therapies and applications, neurological syndromes associated with their use, and risk factors contributing to ICANS.

The effect of cannabidiol on seizure features and quality of life in drug-resistant frontal lobe epilepsy patients: a triple-blind controlled trial.

Background: Treatment-resistant epileptic seizures are associated with reduced quality of life (QoL). As polypharmacy with routine antiseizure medications has many side effects, novel add-on treatments are necessary. Recent research showed the efficacy of add-on therapy by cannabidiol (CBD) on refractory epilepsy. We attempted to extend data on the efficacy and safety profile of CBD in patients with frontal lobe treatment-resistant epilepsy. Methods: A total of 27 patients were recruited into two CBD (n = 12) and placebo (n = 15) groups. The CBD group received a highly purified liposomal preparation of the drug in addition to routine antiseizure medications. The placebo group only received antiseizure medications. This experiment followed a triple-blinding protocol. Outcome measures were seizure frequency, the Chalfont seizure severity scale (CSSS), and the quality of life questionnaire score (QOLIE-31) assessed at baseline, 4 weeks, and 8 weeks. Results: At 4 weeks, results indicated that a higher fraction of patients in the CBD group (66.67%) showed improvement in seizure, compared to the placebo group (20.00%). Before-after comparison revealed that CBD, unlike routine ADEs, was effective in reducing the occurrence of seizures at the study's final timepoint [mean difference 45.58, 95% CI (8.987 to 82.18), p = 0.009]. Seizure severity was not affected by study groups or time intervals (repeated-measures ANOVA p > 0.05). Post-hoc tests found that the QoLI-31 score was improved at 8 weeks compared to baseline [mean diff. -5.031, 95% CI (-9.729 to -0.3328), p = 0.032]. The difference in cases who experienced enhanced QoL was meaningful between the CBD and placebo groups at 8 weeks [RR: 2.160, 95% CI (1.148 to 4.741), p = 0.018] but not at 4 weeks (p = 0.653). A positive finding for QoL improvement was associated with a positive finding for seizure frequency reduction [r = 0.638, 95% CI (0.296 to 0.835), p = 0.001]. Interestingly, limiting the correlation analysis to cases receiving CBD indicated that QoL improvement was not linked with seizure parameters such as severity and frequency (p > 0.05). Conclusion: The present study suggests the benefit of a purified and highly efficient preparation of CBD for seizure frequency reduction and improvement of QoL in refractory frontal lobe epilepsy. Further study with longer follow-ups and larger sample size is advised. Clinical trial registration: https://www.irct.ir/trial/56790, identifier: IRCT20210608051515N1.

Deep brain stimulation (DBS) as a therapeutic approach in gait disorders: What does it bring to the table?

Gait deficits are found in various degenerative central nervous system conditions, and are particularly a hallmark of Parkinson's disease (PD). While there is no cure for such neurodegenerative disorders, Levodopa is considered as the standard medication in PD patients. Often times, the therapy of severe PD consists of deep brain stimulation (DBS) of the subthalamic nucleus. Earlier research exploring the effect of gait have reported contradictory results or insufficient efficacy. A change in gait includes various parameters, such as step length, cadence, Double-stance phase duration which may be positively affected by DBS. DBS could also be effective in correcting the levodopa-induced postural sway abnormalities. Moreover, during normal walking, interaction among the subthalamic nucleus and cortex -essential regions which exert a role in locomotion- are coupled. However, during the freezing of gait, the activity is desynchronized. The mechanisms underlying DBS-induced neurobehavioral improvements in such scenarios requires further study. The present review discusses DBS in the context of gait, the benefits associated with DBS compared to standard pharmacotherapy options, and provides insights into future research.

Determination of plasma transcobalamin-II and zinc levels in newly-diagnosed and long-standing grand mal epileptic patients.

Background: The changes of plasma transcobalamin-II (TCII) and Zinc (Zn) Levels in epileptic patients are not clearly understood. The aim of the current study was to evaluate the plasma contents of TCII and Zn levels in newly-diagnosed epileptic seizure patients, long-standing grand mal epileptic patients following treatment with sodium valproate and healthy control group. Methods: Thirty patients aged 36.76±12.91 years with newly-diagnosed and thirty long-standing grand mal epileptic patients aged 35.56 ±12.77 years were diagnosed based on the clinical symptoms. The control subjects were picked out from healthy individuals and matched to the patients, aged 36.30 ±12.80 years. Plasma Zn and TCN-2 was evaluated via spectrophotometry at 546 nm and 450 nm, respectively, using chimerical kits. Results: Plasma level of TCII in the newly-diagnosed epileptic seizures patients and long-standing grand mal epileptic patients were significantly increased, compared to the healthy controls [14.89 ±3.24 and 21.84± 2.73 vs. 9.55±1.24, (n=30)], respectively. Plasma level of Zn was decreased in the newly-diagnosed epileptic seizure patients, while it was increased in long-standing grand mal epileptic patients compared to the control group [69.28± 6.41 and 80.56 ±6.12 and vs.75.80±1.59, (n=30)], respectively. Conclusion: This study suggests that sodium valproate may disrupt the homeostatic balance of TCII and Zn, and cause abnormality of their serum level in newly-diagnosed epileptic seizure patients and long-standing grand mal epileptic patients. Further research is recommended to identify the underpinning for these changes.

The relationship between long non-coding RNAs and Wnt/ß-catenin signaling pathway in the pathogenesis of Alzheimer's disease.

Long non-coding RNAs (lncRNAs) cannot be coded to proteins; however, they can display important functions in several aspects of cell biology. Their abnormal expression is verified in various disorders, including neurodegenerative diseases, especially Alzheimer's disease (AD). By acting as a cell cycle suppressor or promotor, lncRNAs mediate some signaling pathways, which in turn lead to exacerbation or improvement of AD. Wnt/ß-catenin signaling pathway, as an important pathway in the pathogenesis of AD, can extremely be affected by lncRNAs. This pathway participates in various biological processes, such as embryogenesis and tissue homeostasis, and is involved in expanding the central nervous system, such as synaptogenesis, plasticity, and hippocampal neurogenesis. lncRNAs can regulate the expression of Wnt pathway target genes by interacting with various components of this pathway. This article discusses lncRNAs and their associated mechanisms in the alteration of Wnt/ß-catenin signaling, which can be regarded as a new aspect of diagnosing and treating AD.

Microglia dynamics in aging-related neurobehavioral and neuroinflammatory diseases.

Microglia represent the first line of immune feedback in the brain. Beyond immune surveillance, they are essential for maintaining brain homeostasis. Recent research has revealed the microglial cells' spatiotemporal heterogeneity based on their local and time-based functions in brain trauma or disease when homeostasis is disrupted. Distinct "microglial signatures" have been recorded in physiological states and brain injuries, with discrete or sometimes overlapping pro- and anti-inflammatory functions. Microglia are involved in the neurological repair processes, such as neurovascular unit restoration and synaptic plasticity, and manage the extent of the damage due to their phenotype switching. The versatility of cellular phenotypes beyond the classical M1/M2 classification, as well as the double-edge actions of microglia in neurodegeneration, indicate the need for further exploration of microglial cell dynamics and their contribution to neurodegenerative processes. This review discusses the homeostatic functions of different microglial subsets focusing on neuropathological conditions. Also, we address the feasibility of targeting microglia as a therapeutic strategy in neurodegenerative diseases.

Serum soluble Fas ligand is a severity and mortality prognostic marker for COVID-19 patients.

Finding cytokine storm initiator factors associated with uncontrolled inflammatory immune response is necessary in COVID-19 patients. The aim was the identification of Fas/Fas Ligand (FasL) role in lung involvement and mortality of COVID-19 patients. In this case-control study, mild (outpatient), moderate (hospitalized), and severe (ICU) COVID-19 patients and healthy subjects were investigated. RNA isolated from PBMCs for cDNA synthesis and expression of mFas/mFasL mRNA was evaluated by RT-PCR. Serum sFas/sFasL protein by ELISA and severity of lung involvement by CT-scan were evaluated. Also, we docked Fas and FasL via Bioinformatics software (in silico) to predict the best-fit Fas/FasL complex and performed molecular dynamics simulation (MDS) in hyponatremia and fever (COVID-19 patients), and healthy conditions. mFasL expression was increased in moderate and severe COVID-19 patients compared to the control group. Moreover, mFas expression showed an inverse correlation with myalgia symptom in COVID-19 patients. Elevation of sFasL protein in serum was associated with reduced lung injury and mortality. Bioinformatics analysis confirmed that blood profile alterations of COVID-19 patients, such as fever and hyponatremia could affect Fas/FasL complex interactions. Our translational findings showed that decreased sFasL is associated with lung involvement; severity and mortality in COVID-19 patients. We think that sFasL is a mediator of neutrophilia and lymphopenia in COVID-19. However, additional investigation is suggested. This is the first report describing that the serum sFasL protein is a severity and mortality prognostic marker for the clinical management of COVID-19 patients.

Aging, testosterone, and neuroplasticity: friend or foe?

Neuroplasticity or neural plasticity implicates the adaptive potential of the brain in response to extrinsic and intrinsic stimuli. The concept has been utilized in different contexts such as injury and neurological disease. Neuroplasticity mechanisms have been classified into neuroregenerative and function-restoring processes. In the context of injury, neuroplasticity has been defined in three post-injury epochs. Testosterone plays a key yet double-edged role in the regulation of several neuroplasticity alterations. Research has shown that testosterone levels are affected by numerous factors such as age, stress, surgical procedures on gonads, and pharmacological treatments. There is an ongoing debate for testosterone replacement therapy (TRT) in aging men; however, TRT is more useful in young individuals with testosterone deficit and more specific subgroups with cognitive dysfunction. Therefore, it is important to pay early attention to testosterone profile and precisely uncover its harms and benefits. In the present review, we discuss the influence of environmental factors, aging, and gender on testosterone-associated alterations in neuroplasticity, as well as the two-sided actions of testosterone in the nervous system. Finally, we provide practical insights for further study of pharmacological treatments for hormonal disorders focusing on restoring neuroplasticity.

In silico design of a TLR4-mediating multiepitope chimeric vaccine against amyotrophic lateral sclerosis via advanced immunoinformatics.

Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disorder worldwide. In ALS, progressing disease can result from misfolding and aggregation of superoxide dismutase-1 (SOD1) or TAR DNA-binding protein 43 kDa (TDP43). An efficient immunotherapy for ALS should spare intact SOD1 while eliminating its dysfunctional variant. We utilized advanced immunoinformatics to suggest a potential vaccine candidate against ALS by proposing a model of dynamic TLR4 mediation and induction of a specific Th2-biased shift against mutant SOD1, TDP43, and TRAF6, a protein that specifically interacts with dysfunctional SOD1. SOD1, TDP43, and TRAF6 were retrieved in FASTA. Immune Epitopes Database and CTLpred suggested T/B-cell epitopes from disease-specific regions of selected antigens. A TLR4-mediating adjuvant, RS01, was used. Sequences were assembled via suitable linkers. Tertiary structure of the protein was calculated. Refined protein structure and physicochemical features of the 3D structure were verified in silico. Differential immune induction was assessed via C-ImmSim. GROningen MAchine for Chemical Simulation was used to assess evolution of the docked vaccine-TLR4 complex in blood. Our protein showed high structural quality and was nonallergenic and immune inducing. Also, the vaccine-TLR4 complex stability was verified by RMSD, RMSF, gyration, and visual analyses of the molecular dynamic trajectory. Contact residues in the vaccine-TLR4 complex showed favorable binding energies. Immune stimulation analyses of the proposed candidate demonstrated a sustained memory cell response and a strong adaptive immune reaction. We proposed a potential vaccine candidate against ALS and verified its physicochemical and immune inducing features. Future studies should assess this vaccine in animal studies.

Engineering a novel immunogenic chimera protein utilizing bacterial infections associated with atherosclerosis to induce a deviation in adaptive immune responses via Immunoinformatics approaches.

Recent studies have established the role of bacteria including Streptococcus pneumoniae, Helicobacter pylori, Chlamydia pneumonia, Mycobacterium tuberculosis, and Porphyromonas gingivalis in the development of atherosclerosis. These bacteria contribute to plaque formation via promoting Th1 immune responses and speeding up ox-LDL formation. Hence, we employed computational reverse vaccinology (RV) approaches to deviate immune response toward Th2 via engineering a novel immunogenic chimera protein. Prominent atherogenic antigens from related bacteria were identified. Then, machine learning-based servers were employed for predicting CTL and HTL epitopes. We selected epitopes from a wide variety of HLAs. Then, a chimeric protein sequence containing TAT peptide, adjuvant, IL-10 inducer, and linker-separated epitopes was designed. The conformational structure of the vaccine was built via multiple-template homology modelling using MODELLER. The initial structure was refined and validated by Ramachandran plot. The vaccine was also docked with TLR4. After that, molecular dynamics (MD) simulation of the docked vaccine-TLR4 was conducted. Finally, the immune simulation of the vaccine was conducted via the C-ImmSim server. A chimera protein with 629 amino acids was built and, classified as a non-allergenic probable antigen. An improved ERRAT score of 80.95 for the refined structure verified its stability. Additionally, validation via the Ramachandran plot showed 98.09% of the residues were located in the most favorable and permitted regions. MD simulations showed the vaccine-TLR4 complex reached a stable conformation. Also, RMS fluctuations analysis revealed no sign of protein denaturation or unfolding. Finally, immune response simulations indicated a promising response by innate and adaptive immunity. In summary, we built an immunogenic vaccine against atherosclerosis and demonstrated its favorable properties via advanced Immunoinformatics analyses. This study may pave the path for combat against atherosclerosis.

Early environmental enrichment prevents cognitive impairments and developing addictive behaviours in a mouse model of prenatal psychological and physical stress.

Environmental enrichment (EE) has shown remarkable effects in improving cognition and addictive behaviour. We tested whether EE could help recover from prenatal stress exposure. Mature Swiss Webster male and virgin female mice were placed together until vaginal plugs were detectable. Next, pregnant rodents were randomized into the control, physically and psychologically stressed groups. The application of stress was initiated on the 10th day of pregnancy and persisted for a week to induce stress in the mice. Open field and elevated plus-maze (EPM) tests were utilized as explorative and anxiety assays, respectively. A passive avoidance shuttle-box test was carried out to check anxiety-modulated behaviour. Morris water maze (MWM) test was undertaken to evaluate spatial learning and memory. Conditioned place preference (CPP) test was selected for evaluation of tendency to morphine consumption. Our results showed that prenatal stress elevated anxiety-like behaviour in the offspring which EE could significantly alleviate after weaning. We also found a higher preference for morphine use in the physical stress and psychological stress offspring group. However, no difference was observed among the genders. Application of EE for the stress group improved several parameters of the cognitive behaviour significantly. Although prenatal stress can lead to detrimental behavioural and cognitive outcomes, it can in part be relieved by early exposure to EE. However, some outcomes linked to prenatal stress exposure may not be diminished by EE therapy. In light of such irreversible effects, large-scale preventive actions promoting avoidance from stress during pregnancy should be advised.

Indomethacin attenuates neuroinflammation and memory impairment in an STZ-induced model of Alzheimer's like disease.

Objective: Non-steroidal anti-inflammatory drugs (NSAIDs) exposure might be considerably associated with a decreased risk of Alzheimer's disease (AD). Therefore, we conducted an experiment to investigate the impact of indomethacin (IND) on inflammasome as a key player of neuroinflammation.Methods: The Alzheimer's-like condition was induced by streptozotocin (STZ) in rats. IND was injected intraperitoneally 1 d prior to STZ administration and resumed with 2 d interval up to 60 d. Morris water maze (MWM) was utilized to assess learning and memory. The expression level of genes that contribute to the inflammasome pathway was measured using real-time polymerase chain reaction (PCR). To authenticate the obtained outcomes, immunostaining for caspase-1, interleukin-1ß (IL-1ß), and phosphorylated tau (p-Tau) protein was conducted.Results: Behavioral experiments indicated that IND treatment was able to improve learning and memory performance (p<.05). A significant decrease in C-terminal caspase recruitment domain [CARD] domain-containing protein 4 (NLRC4), nucleotide-binding oligomerization domain [NOD]-like receptor protein 3 (NLRP3), IL-1ß, and apoptosis-associated speck-like protein containing CARD (ASC) mRNA expression was recorded in IND administered group compared with the STZ group (p<.05). Furthermore, expression levels of IL-18 and caspase-1 in the hippocampus of IND-treated group tended to decrease. Immunostaining evaluations showed that few positive cells for caspase-1, IL-1ß, and p-Tau protein in IND treated animals, whereas the number of positive cells was considerably increased in STZ treated animals (p<.05).Conclusion: It could be deduced that IND improves neuroinflammation and memory impairment in AD through decreasing IL-1ß and caspase-1 that are associated with suppression of NLRC4 and NLRP3 inflammasome genes. This holds the potential to introduce valuable targets in the field for successful combat against AD.

Addiction and the cerebellum with a focus on actions of opioid receptors.

Increasing evidence suggests that the cerebellum could play a role in the higher cognitive processes involved in addiction as the cerebellum contains anatomical and functional pathways to circuitry controlling motivation and saliency. In addition, the cerebellum exhibits a widespread presence of receptors, including opioid receptors which are known to play a prominent role in synaptic and circuit mechanisms of plasticity associated with drug use and development of addiction to opioids and other drugs of abuse. Further, the presence of perineural nets (PNNs) in the cerebellum which contain proteins known to alter synaptic plasticity could contribute to addiction. The role the cerebellum plays in processes of addiction is likely complex, and could depend on the particular drug of abuse, the pattern of use, and the stage of the user within the addiction cycle. In this review, we discuss functional and structural modifications shown to be produced in the cerebellum by opioids that exhibit dependency-inducing properties which provide support for the conclusion that the cerebellum plays a role in addiction.

Triangle of cytokine storm, central nervous system involvement, and viral infection in COVID-19: the role of sFasL and neuropilin-1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is identified as the cause of coronavirus disease 2019 (COVID-19), and is often linked to extreme inflammatory responses by over activation of neutrophil extracellular traps (NETs), cytokine storm, and sepsis. These are robust causes for multi-organ damage. In particular, potential routes of SARS-CoV2 entry, such as angiotensin-converting enzyme 2 (ACE2), have been linked to central nervous system (CNS) involvement. CNS has been recognized as one of the most susceptible compartments to cytokine storm, which can be affected by neuropilin-1 (NRP-1). ACE2 is widely-recognized as a SARS-CoV2 entry pathway; However, NRP-1 has been recently introduced as a novel path of viral entry. Apoptosis of cells invaded by this virus involves Fas receptor-Fas ligand (FasL) signaling; moreover, Fas receptor may function as a controller of inflammation. Furthermore, NRP-1 may influence FasL and modulate cytokine profile. The neuroimmunological insult by SARS-CoV2 infection may be inhibited by therapeutic approaches targeting soluble Fas ligand (sFasL), cytokine storm elements, or related viral entry pathways. In the current review, we explain pivotal players behind the activation of cytokine storm that are associated with vast CNS injury. We also hypothesize that sFasL may affect neuroinflammatory processes and trigger the cytokine storm in COVID-19.