Kolaviron neuroprotective effect against okadaic acid-provoked cognitive impairment.

Alzheimer's disease (AD) is acknowledged as the main causative factor of dementia that affects millions of people around the world and is increasing at increasing pace. Okadaic acid (OA) is a toxic compound with ability to inhibit protein phosphatases and to induce tau protein hyperphosphorylation and Alzheimer's-like phenotype. Kolaviron (KV) is a bioflavonoid derived from Garcinia kola seeds with anti-antioxidative and anti-inflammation properties. The main goal of this study was to assess whether kolaviron can exert neuroprotective effect against okadaic acid-induced cognitive deficit. Rats had an intracerebroventricular (ICV) injection of OA and pretreated with KV at 50 or 100 mg/kg and examined for cognition besides histological and biochemical factors. OA group treated with KV at 100 mg/kg had less memory deficit in passive avoidance and novel object discrimination (NOD) tasks besides lower hippocampal levels of caspases 1 and 3, tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) as inflammatory factors, reactive oxygen species (ROS), protein carbonyl, malondialdehyde (MDA), and phosphorylated tau (p-tau) and higher level of acetylcholinesterase (AChE) activity, mitochondrial integrity index, superoxide dismutase (SOD), and glutathione (GSH). Moreover, KV pretreatment at 100 mg/kg attenuated hippocampal CA1 neuronal loss and glial fibrillary acidic protein (GFAP) reactivity as a factor of astrogliosis. In summary, KV was able to attenuate cognitive fall subsequent to ICV OA which is partly mediated through its neuroprotective potential linked to mitigation of tau hyperphosphorylation, apoptosis, pyroptosis, neuroinflammation, and oxidative stress and also improvement of mitochondrial health.

High and Low-Frequency Stimulation Effect on Epileptiform Activity in Brain Slices.

Background: Neurostimulation is one of the new therapeutic approaches in patients with drug-resistant epilepsy, and despite its high efficiency, its mechanism of action is still unclear. On the one hand, electrical stimulation in the human brain is immoral; on the other hand, the creation of the epilepsy model in laboratory animals affects the entire brain network. As a result, one of the ways to achieve the neurostimulation mechanism is to use epileptiform activity models In vitro. In vitro models, by accessing the local network from the whole brain, we can understand the mechanisms of action of neurostimulation. Methods: A literature search using scientific databases including PubMed, Google Scholar, and Scopus, using "Neurostimulation" and "epileptiform activity" combined with "high-frequency stimulation", " low-frequency stimulation ", and "brain slices" as keywords were conducted, related concepts to the topic gathered and are used in this paper. Results: Electrical stimulation causes neuronal depolarization and the release of GABAA, which inhibits neuronal firing. Also, electrical stimulation inhibits the nervous tissue downstream of the stimulation site by preventing the passage of nervous activity from the upstream to the downstream of the axon. Conclusion: Neurostimulation techniques consisting of LFS and HFS have a potential role in treating epileptiform activity, with some studies having positive results. Further investigations with larger sample sizes and standardized outcome measures can be conducted to validate the results of previous studies.

Astaxanthin ameliorates spinal cord edema and astrocyte activation via suppression of HMGB1/TLR4/NF-κB signaling pathway in a rat model of spinal cord injury.

Spinal cord edema is a quick-onset phenomenon with long-term effects. This complication is associated with inflammatory responses, as well as poor motor function. No effective treatment has been developed against spinal edema, which urges the need to provide novel therapies. Astaxanthin (AST) is a fat-soluble carotenoid with anti-inflammatory effects and a promising candidate for treating neurological disorders. This study aimed to investigate the underlying mechanism of AST on the inhibition of spinal cord edema, astrocyte activation, and reduction of inflammatory responsesin a rat compression spinal cord injury (SCI) model. Male rats underwent laminectomy at thoracic 8-9, and the SCI model was induced using an aneurysm clip. After SCI, rats received dimethyl sulfoxide or AST via intrathecal injection. The effects of AST were examined on the motor function, spinal cord edema, integrity of blood-spinal cord barrier (BSCB), and expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), glial fibrillary acidic protein (GFAP), and aquaporin-4 (AQP4), and matrix metallopeptidase- 9 (MMP-9) post-SCI. We showed that AST potentially improved the recovery of motor function and inhibited the spinal cord edema via maintaining the integrity of BSCB, reducing the expression of HMGB1, TLR4, and NF-κB, MMP-9 as well as downregulation of astrocyte activation (GFAP) and AQP4 expression. AST improves motor function and reduces edema and inflammatory responses in the spinal tissue. These effects are mediated by suppression of the HMGB1/TLR4/NF-κB signaling pathway, suppressing post-SCI astrocyte activation, and decreasing AQP4 and MMP-9 expression.

Acamprosate effect on neuropathic pain in rats: With emphasis on the role of ERK/MAPK pathway and SCN9A sodium channel.

BACKGROUND: Neuropathic pain is a chronic pain owing to nerve damage or diseases of the central nervous system (CNS). The expression of SCN9A, which encodes the Nav1.7 voltage-gated sodium channel and ERK have been found to change significantly in many cases of neuropathic pain. Here, we investigated effects of acamprosate on neuropathic pain, taking into account the crucial roles of SCN9A, the ERK signaling pathway, and inflammatory markers in a rat model of chronic constriction injury (CCI). METHODS: Acamprosate (300 mg/kg) was injected intraperitoneally (i.p.) for 14 days. The tail-immersion, acetone, and formalin tests were used to determine behavioral tests such as heat allodynia, cold allodynia, and chemical hyperalgesia, respectively. Lumbar spinal cord was extracted and processed for Nissl staining. The amount of spinal SCN9A expression and ERK phosphorylation were examined using ELISA assay. RESULTS: The expression of SCN9A, ERK, inflammatory cytokines (IL-6 and TNF-α), allodynia and hyperalgesia significantly increased on days 7 and 14 following CCI. The treatment not only reduced neuropathic pain but also blocked CCI's effects on SCN9A upregulation and ERK phosphorylation. CONCLUSION: This research demonstrated that acamprosate reduces the neuropathic pain induced by CCI of the sciatic nerve in rats by preventing cell loss, inhibiting spinal SCN9A expression, ERK phosphorylation, and inflammatory cytokines, suggesting potential therapeutic implications of acamprosate administration for the treatment of neuropathic pain.

A photoactive injectable antibacterial hydrogel to support chemo-immunotherapeutic effect of antigenic cell membrane and sorafenib by near-infrared light mediated tumor ablation.

Intravenously administered nanocarriers suffer from off-target distribution, pre-targeting drug leakage, and rapid clearance, limiting their efficiency in tumor eradication. To bypass these challenges, an injectable hydrogel with time- and temperature-dependent viscosity enhancement behavior and self-healing property are reported to assist in the retention of the hydrogel in the tumor site after injection. The cancer cell membrane (CCM) and sorafenib are embedded into the hydrogel to elicit local tumor-specific immune responses and induce cancer cell apoptosis, respectively. In addition, hyaluronic acid (HA) coated Bi2S3 nanorods (BiH) are incorporated within the hydrogel to afford prolonged multi-cycle local photothermal therapy (PTT) due to the reduced diffusion of the nanorods to the surrounding tissues as a result of HA affinity toward cancer cells. The results show the promotion of immunostimulatory responses by both CCM and PTT through the release of inflammatory cytokines from immune cells, which allows localized and complete ablation of the breast tumor in an animal model by a single injection of the hydrogel. Moreover, the BiH renders strong antibacterial activity to the hydrogel, which is crucial for the clinical translation of injectable hydrogels as it minimizes the risk of infection in the post-cancer lesion formed by PTT-mediated cancer therapy.

Role of P11 through serotonergic and glutamatergic pathways in LID.

Parkinson's disease is a progressive neurodegenerative disorder caused by the degeneration of dopaminergic neurons. This leads to the pathogenesis of multiple basal ganglia-thalamomotor loops and diverse neurotransmission alterations. Dopamine replacement therapy, and on top of that, levodopa and l-3,4-dihydroxyphenylalanine (L-DOPA), is the gold standard treatment, while it develops numerous complications. Levodopa-induced dyskinesia (LID) is well-known as the most prominent side effect. Several studies have been devoted to tackling this problem. Studies showed that metabotropic glutamate receptor 5 (mGluR5) antagonists and 5-hydroxytryptamine receptor 1B (5HT1B) agonists significantly reduced LID when considering the glutamatergic overactivity and compensatory mechanisms of serotonergic neurons after L-DOPA therapy. Moreover, it is documented that these receptors act through an adaptor protein called P11 (S100A10). This protein has been thought to play a crucial role in LID due to its interactions with numerous ion channels and receptors. Lately, experiments have shown successful evidence of the effects of P11 blockade on alleviating LID greater than 5HT1B and mGluR5 manipulations. In contrast, there is a trace of ambiguity in the exact mechanism of action. P11 has shown the potential to be a promising target to diminish LID and prolong L-DOPA therapy in parkinsonian patients owing to further studies and experiments.

Regional cerebral blood flow and brain atrophy in mild cognitive impairment and Alzheimer's disease.

Objectives: A decline in the regional cerebral blood flow (CBF) is proposed to be one of the initial changes in the Alzheimer's disease process. To date, there are limited data on the correlation between CBF decline and gray matter atrophy in mild cognitive impairment (MCI) and AD patients. to investigate the association between CBF with the gray matter structural parameters such as cortical volume, surface area, and thickness in AD, MCI, and healthy controls (HC). Methods: Data from three groups of participants including 39 HC, 82 MCI, and 28 AD subjects were obtained from the Alzheimer's disease Neuroimaging Initiative (ADNI). One-way ANOVA and linear regression were used to compare data and find a correlation between structural parameters such as cortical volume, surface area, and thickness and CBF which measured by arterial spin labeling (ASL)-MRI. Results: Our findings revealed a widespread significant correlation between the CBF and structural parameters in temporal, frontal, parietal, occipital, precentral gyrus, pericalcarine cortex, entorhinal cortex, supramarginal gyrus, fusiform, precuneus, and pallidum. Conclusion: CBF decline may be a useful biomarker for MCI and AD and accurately reflect the structural changes related to AD. According to the present results, CBF decline, as measured by ASL-MRI, is correlated with lower measures of structural parameters in AD responsible regions. It means that CBF decline may reflect AD-associated atrophy across disease progression and is also used as an early biomarker for AD and MCI diagnosis.

Preliminary report of Iranian Registry of Alzheimer's disease in Tehran province: A cross-sectional study in Iran.

Background and Aims: Alzheimer's disease (AD) is the main cause of dementia and over the 55 million people live with dementia worldwide. We aimed to establish the first database called the Iranian Alzheimer's Disease Registry to create a powerful source for future research in the country. In this report, the design and early results of the Iranian Alzheimer's Disease Registry will be described. Methods: We performed this multicenter investigation and patients' data including age, sex, educational level, disease status, Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS) from 2018 to 2021 were collected, registered, and analyzed by GraphPad Prism software. Results: Totally 200 AD patients were registered in our database. 107 (54%) were women and age of 147 (74%) were over 65. The mean age for men and women was 76.20 ± 8.29 and 76.40 ± 8.83 years, respectively. 132 (66%) were married and 64 (32%) were illiterate. Also, 94 (47%) were in the moderate stage of disease, and 150 (75%) lived at home together with their families. The most frequent neurological comorbidity was psychosis (n = 72, 36%), while hypertension was the most common non-neurological comorbidity (n = 104, 52%). The GDS score of women in the mild stage (5.23 ± 2.9 vs. 6.9 ± 2.6, p = 0.005) and moderate stage (5.36 ± 2.4 vs. 8.21 ± 2.06, p = <0.001) of the disease was significantly greater than men. In univariate analysis, MMSC score was remarkably associated with stroke (ß = -2.25, p = 0.03), psychosis (ß = -2.18, p = 0.009), diabetes (ß = 3.6, p = <0.001), and hypercholesteremia (ß = 1.67, p = 0.05). Also, the MMSE score showed a notable relationship with stroke (ß = -2.13, p = 0.05) and diabetes (ß = 3.26, p = <0.001) in multivariate analysis. Conclusion: Iranian Alzheimer's Disease Registry can provide epidemiological and clinical data to use for purposes such as enhancing the current AD management in clinical centers, filling the gaps in preventative care, and establishing effective monitoring and cure for the disease.

Astaxanthin Modulates Autophagy, Apoptosis, and Neuronal Oxidative Stress in a Rat Model of Compression Spinal Cord Injury.

The effects of astaxanthin (AST) were evaluated on oxidative mediators, neuronal apoptosis, and autophagy in functional motor recovery after spinal cord injury (SCI). Rats were divided into three groups of sham, SCI + DMSO (dimethyl sulfoxide), and SCI + AST. Rats in the sham group only underwent a laminectomy at thoracic 8-9. While, the SCI + DMSO and SCI + AST groups had a compression SCI with an aneurysm clip. Then, this groups received an intrathecal (i.t.) injection of 5% DMSO and AST (10 µl of 0.005 mg/kg), respectively. The rat motor functions were assessed weekly until the 28th day using a combined behavioral score (CBS). Total antioxidant capacity (TAC), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were measured in spinal tissue to evaluate oxidative stress-related parameters. Besides, autophagy-related proteins (P62, LC3B, and Beclin1) and apoptosis-associated proteins (Bax and Bcl2) were determined using western blotting on the 1st and 7th days after surgery. Hematoxylin-eosin and Fluoro-Jade B staining were performed to detect the histological alterations and neuronal degeneration. As the result, treatment with AST potentially attenuated rat CBS scores (p < 0.001) towards a better motor performance. AST significantly reduced the spinal level of oxidative stress by increasing TAC, SOD, and GPx, while decreasing MDA (p < 0.001). Furthermore, AST treatment remarkably upregulated expression of LC3B (p < 0.001), and Beclin1 (p < 0.05) in the spinal cord, but downregulated P62 (p < 0.05) and the Bax/Bcl2 ratio (p < 0.001). Consequently, AST reduced SCI-induced histological alterations and neuronal degeneration (p < 0.001). In conclusion, AST can improve motor function after SCI by reducing oxidative stress/apoptosis and increasing neuronal autophagy.

The Roles of Serotonin in Neuropsychiatric Disorders.

The serotonergic system extends throughout the central nervous system (CNS) and the gastrointestinal (GI) tract. In the CNS, serotonin (5-HT, 5-hydroxytryptamine) modulates a broad spectrum of functions, including mood, cognition, anxiety, learning, memory, reward processing, and sleep. These processes are mediated through 5-HT binding to 5-HT receptors (5-HTRs), are classified into seven distinct groups. Deficits in the serotonergic system can result in various pathological conditions, particularly depression, schizophrenia, mood disorders, and autism. In this review, we outlined the complexity of serotonergic modulation of physiologic and pathologic processes. Moreover, we provided experimental and clinical evidence of 5-HT's involvement in neuropsychiatric disorders and discussed the molecular mechanisms that underlie these illnesses and contribute to the new therapies.

Hippocampal chloride transporter KCC2 contributes to excitatory GABA dysregulation in the developmental rat model of schizophrenia.

Recent studies have revealed an altered expression of NKCC1 and KCC2 in prefrontal cortex (PFC) and hippocampus of schizophrenic patients. Despite extensive considerations, the alteration of NKCC1 and KCC2 co-transporters at different stages of development has not been fully studied. Therefore, we evaluated the expression of these transporters in PFC and hippocampus at time points of four, eight, and twelve weeks in post-weaning social isolation rearing rat model. For this purpose, 23-25 days-old rats were classified into social- or isolation-reared groups. The levels of NKCC1 and KCC2 mRNA expression were evaluated at hippocampus or PFC regions at the time-points of four, eight, and twelve weeks following housing. Post-weaning isolation rearing decreased the hippocampal KCC2 mRNA expression level, but does not affect the NKCC1 mRNA expression. However, no significant difference was observed in the PFC mRNA levels of NKCC1 and KCC2 in the isolation-reared group compared to the socially-reared group during the course of modeling. Further, we assessed the therapeutic effect of selective NKCC1 inhibitor bumetanide (10 mg/kg), on improvement of prepulse inhibition (PPI) test on twelve weeks isolation-reared rats. Intraperitoneal administration of bumetanide (10 mg/kg) did not exert beneficial effects on PPI deficit. Our findings show that isolation rearing reduces hippocampal KCC2 expression level and may underlie hippocampal GABA excitatory. In addition, 10 mg/kg bumetanide is not effective in improving the reduced PPI of twelve weeks isolation-reared rats. Collectively, our findings show that hippocampal chloride transporter KCC2 contributes to excitatory GABA dysregulation in the developmental rat model of schizophrenia.

Nicotine and modafinil combination protects against the neurotoxicity induced by 3,4-Methylenedioxymethamphetamine in hippocampal neurons of male rats.

MDMA (3,4-Methylenedioxymethamphetamine) is a common recreational drug of abuse which causes neurodegeneration. Nicotine and modafinil provide antioxidant and neuroprotective properties and may be beneficial in the management of MDMA-induced neurotoxicity. The purpose of this study was to characterize how acute and chronic administration of nicotine and/or modafinil exert protective effects against the MDMA-induced impaired cognitive performance, oxidative stress, and neuronal loss. Adult male rats were divided into three groups, namely control, MDMA and treatment (modafinil and/or nicotine). MDMA (10 mg/kg) was administered intraperitoneally during a three-week schedule (two times/day for two consecutive days/week). The treated-groups were classified based on the acute or chronic status of treatment. In the groups which underwent acute treatments, nicotine (0.5 mg/kg) and/or modafinil (100 mg/kg) were injected just prior to the MDMA administration (acute nicotine (NA), acute modafinil (MA), and acute nicotine and modafinil (NMA)). In the rats which received chronic treatments, nicotine (0.5 mg/kg) and/or modafinil (100 mg/kg) were injected every day during the three week-schedule administration of MDMA (chronic nicotine (NC), chronic modafinil (MC), and chronic nicotine and modafinil (NMC)). Learning and memory performance, as well as avoidance response, were assessed by Morris water maze and Shuttle box, respectively. Our findings indicate enhanced learning and memory and avoidance response in the NMC group. By TUNEL test and Cresyl Violet staining we evaluated neuronal loss and apoptosis in the hippocampal CA1 and found increased neuronal viability in the NMC group. On the other hand, chronic administration of modafinil and nicotine significantly down-regulated the caspase 3 and up-regulated both BDNF and TrkB levels in the MDMA-received rats. The serum levels of glutathione peroxidase (GPx) and total antioxidant capacity (TAC) were evaluated and we found that the alterations of serum levels of GPx and TAC were considerably prevented in the NMC group. The overall results indicate that nicotine and modafinil co-administration rescued brain from MDMA-induced neurotoxicity. We suggest that nicotine and modafinil combination therapy could be considered as a possible treatment to reduce the neurological disorders induced by MDMA.

Acetyl-L-carnitine confers neuroprotection against lipopolysaccharide (LPS) -induced neuroinflammation by targeting TLR4/NFκB, autophagy, inflammation and oxidative stress.

Acetyl-L-carnitine has been shown to exert neuroprotection against neurodegenerative diseases. The present study was performed to evaluate neuroprotection effects of acetyl-L-carnitine against lipopolysaccharide (LPS) -induced neuroinflammation and clarify possible mechanisms. A single dose (500 µg/kg) of LPS was intraperitoneally injected to rats to induce model. The animals were intraperitoneally treated with different doses of acetyl-L-carnitine (30, 60, and 100) for 6 days. Y-maze task, single-trial passive avoidance and novel object recognition tests were used to evaluate memory impairments. ELISA assay was used to evaluate the expression of TLR4/NFκB, autophagic and oxidative stress markers. Our result showed that intraperitoneal injection of LPS resulted in initiation of neuroinflammation by activation of TLR4/NFκB, suppression of autophagic markers such as LC3 II/ LC3 I ratio and becline-1, and excessive production of ROS and MDA. Intraperitoneal administration of acetyl-L-carnitine contributed to neuroprotection against LPS -induced neuroinflammation by suppression of TLR4/NFκB pathway, restoring activity of autophagy and inhibition of oxidative stress. Collectively, our findings show that acetyl-L-carnitine attenuated LPS-induced neuroinflammation by targeting TLR4/NFκB pathway, autophagy and oxidative stress.

Hepatocyte Growth Factor Attenuates the Severity of Status Epilepticus in Kainic Acid-induced Model of Temporal Lobe Epilepsy by Targeting Apoptosis and Astrogliosis.

Introduction: Although pharmacotherapy is the most common treatment for epilepsy, proper seizure control is not achieved with current medications. This study evaluated the protective effects of the Hepatocyte Growth Factor (HGF) in a rat model of Temporal Lobe Epilepsy (TLE) and explored possible molecular mechanisms. Methods: A TLE rat model was determined using an intra-hippocampal kainic acid injection (4 µg). Intra-cerebrovascular injection of HGF (6 µg) was performed 30 min before kainic acid injection. Learning and memory impairment were investigated by behavioral tests. The Enzyme-Linked Immunosorbent (ELISA) was used to determine astrogliosis and DNA fragmentation. Changes in neuronal density and mossy fiber sprouting were evaluated by Nissl and Timm staining, respectively. Results: Behavioral assessments indicated that kainate-treated rats presented spontaneous seizures. Moreover, their alternation percentage scores in the Y-Maze test were lower (P<0.001). Likewise, the passive avoidance test confirmed learning disability in Kainate-treated rats (P<0.001). HGF administration reduced the number of spontaneous seizures, alternation percentage score (P<0.001), and cognitive disturbances (P<0.001). The histopathological results also showed that a protected HGF administration contributed to the reduction of neuronal loss in the CA3 subregion of the hippocampus and inhibited the formation of aberrant Mossy Fiber Sprouting (MFS) (P<0.01). Furthermore, the ELISA data indicated a significant decrease in GFAP (P<0.01) and DNA fragmentation (P<0.05) following HGF administration. Conclusion: Our findings demonstrated the validity of HGF in protection against the progression of the kainate-induced TLE in rats. This measure improved learning, cognitive disturbances and inhibited apoptosis and astrogliosis. Highlights: Temporal lobe epilepsy results in apoptosis of neuronal cells;Hepatocyte growth factor attenuates the severity of status epilepticus in kainic acid-induced model;Hepatocyte growth factor attenuates apoptosis of neuronal cells in kainic acid-induced model of temporal lobe epilepsy. Plain Language Summary: Epilepsy is known as a disorder of the CNS which is caused by an imbalance in the electrical activity of neurons that in turn results in derangement in cognitive or causing debilitating seizures. Hepatocyte growth factor is one of neurotrophins secreted from mesenchymal and epithelial cells that regulate the growth, survival and functional changes of cells through signaling pathways such as the tyrosine kinase pathway after binding to its specific receptor. In this study, we tried to find out the effect of hepatocyte growth factor on attenuation of the severity of status epilepticus in kainic acid-induced model of temporal lobe epilepsy. Our results show that hepatocyte growth factor is able to protect against progression of the kainate-induced temporal lobe epilepsy in rats by improvement of learning, cognitive disturbances and inhibiting of apoptosis and astrogliosis.

Combination Therapy of Killing Diseases by Injectable Hydrogels: From Concept to Medical Applications.

The complexity of hard-to-treat diseases strongly undermines the therapeutic potential of available treatment options. Therefore, a paradigm shift from monotherapy toward combination therapy has been observed in clinical research to improve the efficiency of available treatment options. The advantages of combination therapy include the possibility of synchronous alteration of different biological pathways, reducing the required effective therapeutic dose, reducing drug resistance, and lowering the overall costs of treatment. The tunable physical properties, excellent biocompatibility, facile preparation, and ease of administration with minimal invasiveness of injectable hydrogels (IHs) have made them excellent candidates to solve the clinical and pharmacological limitations of present systems for multitherapy by direct delivery of therapeutic payloads and improving therapeutic responses through the formation of depots containing drugs, genes, cells, or a combination of them in the body after a single injection. In this review, currently available methods for the design and fabrication of IHs are systematically discussed in the first section. Next, as a step toward establishing IHs for future multimodal synergistic therapies, recent advances in cancer combination therapy, wound healing, and tissue engineering are addressed in detail in the following sections. Finally, opportunities and challenges associated with IHs for multitherapy are listed and further discussed.

The Interplay of Tau Protein and ß-Amyloid: While Tauopathy Spreads More Profoundly Than Amyloidopathy, Both Processes Are Almost Equally Pathogenic.

Alzheimer's disease (AD) is a neurodegenerative disorder, in which amyloid precursor protein (APP) misprocessing and tau protein hyperphosphorylation are well-established pathogenic cascades. Despite extensive considerations, the central mediator of neuronal cell death upon AD remains under debate. Therefore, we examined the direct interplay between tauopathy and amyloidopathy processes. We employed primary culture neurons and examined pathogenic P-tau and Aß oligomers upon hypoxia treatment by immunofluorescence and immunoblotting. We observed both tauopathy and amyloidopathy processes upon the hypoxia condition. We also applied Aß1-42 or P-tau onto primary cultured neurons. We overexpressed P-tau in SH-SY5Y cells and found Aß accumulation. Furthermore, adult male rats received Aß1-42 or pathogenic P-tau in the dorsal hippocampus and were examined for 8 weeks. Learning and memory performance, as well as anxiety behaviors, were assessed by Morris water maze and elevated plus-maze tests. Both Aß1-42 and pathogenic P-tau significantly induced learning and memory deficits and enhanced anxiety behavior after treatment 2 weeks. Aß administration induced robust tauopathy distribution in the cortex, striatum, and corpus callosum as well as CA1. On the other hand, P-tau treatment developed Aß oligomers in the cortex and CA1 only. Our findings indicate that Aß1-42 and pathogenic P-tau may induce each other and cause almost identical neurotoxicity in a time-dependent manner, while tauopathy seems to be more distributable than amyloidopathy.

Thermo-responsive chitosan hydrogel for healing of full-thickness wounds infected with XDR bacteria isolated from burn patients: In vitro and in vivo animal model.

Treatment of non-healing skin wounds infected with extensively drug-resistant (XDR) bacteria remains as a big challenge. To date, different biomaterials have been applied for treatment of post-wound infections, nevertheless their efficacy for treatment of the wounds infected with XDR isolates has not been determined yet. In this study, the potential of the thermo-responsive chitosan (TCTS) hydrogel for protection of full-thickness wounds XDR bacteria isolated from burn patients was evaluated both in vitro and in vivo in a rat model. Antibacterial activity of the TCTS hydrogel against standard strain and clinical isolates of Acinetobacter baumannii, cytobiocompatibility for Hu02 fibroblast cells, degradation rate and swelling ratio were determined in vitro. MTT assay and disk diffusion test indicated no detectable cytotoxicity and antibacterial activity in vitro, respectively. In vivo study showed significant acceleration of wound healing, re-epithelialization, wound closure, and decreased colony count in the TCTS hydrogel group compared with control. This study suggests TCTS hydrogel as an excellent wound dressing for management of the wounds infected with XDR bacteria, and now promises to proceed with clinical investigations.

Valproic acid administration exerts protective effects against stress-related anhedonia in rats.

Anhedonia or inability to experience pleasure is the sign of various neuropsychiatric conditions. Current treatment options do not provide adequate control of anhedonia. The present study was conducted to evaluate the protective effects of valproic acid (VPA) as a nonspecific histone deacetylase (HDAC) inhibitor to reverse the effects of stress on induction of anhedonia and explore possible mechanisms. To induce anhedonia, a rat model of chronic unpredictable mild stress (CUMS) was established. Animals were assigned into no stress, stress (6 weeks of CUMS) and two treatment groups. VPA treatment was carried out for 4 continuous weeks (200 mg/kg/day). Behavioral assessments were performed using sucrose consumption (SCT) and new object recognition (NOR) tests. The expression of genes was evaluated using qRT-PCR. The cell density was determined using Nissl staining. Rats with CUMS showed depressive-like behaviors and impaired memory performance compared with the non-stressed group (p < 0.01). Moreover, they had significantly higher levels of HDAC3 and MC4R expression in the nucleus accumbens (NAc) compared to the non-stressed group (p < 0.01). The NAc cell density was significantly higher in the non-stressed rats (p < 0.05). Corticosterone plasma level was increased in the CUMS compared to the non-stressed group (p < 0.05). In the CUMS + VPA subgroup, the corticosterone (CORT) plasma level was lower compared with the CUMS + Saline and/or the CUMS groups (p < 0.05). These findings suggest that VPA can improve anhedonia and stress. Although the protective effect of VPA might link to decreasing HDAC3 and MC4R genes expression in NAc.