Astragaloside IV plays a neuroprotective role by promoting PPARγ in cerebral ischemia-reperfusion rats.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) usually occurs during the treatment phase of ischemic disease, which is closely related to high morbidity and mortality. Promoting neurogenesis and synaptic plasticity are effective neural recovery strategies for CIRI. Astragaloside IV (AS-IV) has been shown to play a neuroprotective role in some neurological diseases. In the current study, we evaluated the effect and possible mechanism of AS-IV in CIRI rats. METHODS: The middle cerebral artery occlusion reperfusion (MCAO/R) model was established in rats to simulate the occurrence of human CIRI. First, we determined the cerebral injury on the 1st, 3rd, 5th and 7th day after cerebral ischemia-reperfusion (I/R) surgery by neurological deficit detection, TTC staining, TUNEL staining and Western blot analysis. Furthermore, rats were pre administered with AS-IV and then subjected to cerebral I/R surgery. Brains were collected on the 3rd day to evaluate the neuroprotective effect of AS-IV. RESULTS: Our results showed that on the 3rd day after I/R, the neurological impairment score and infarct volume were highest, the levels of apoptosis and expression of Caspase3 and Bax reached the peak. AS-IV treatment apparently attenuated neurological dysfunction, reduced infarct volume and pathological damage, promoted the neurogenesis, and alleviated the pathological damage caused by cerebral I/R involved in thickening and blurring of synaptic membranes, reduction of microtubules and synaptic vesicles, and loss of synaptic cleft. Our study also showed that AS-IV promoted the transcription and expression of the peroxisome proliferators-activated receptors γ (PPARγ) and brain-derived neurotrophic factor (BDNF), increased the expression of phosphorylation of tyrosine kinase receptor B (TrkB) and downstream PI3K/Akt/mTOR pathway proteins. Notably, when GW9662, an inhibitor of PPARγ was administered with AS-IV, the neuroprotective effect of AS-IV was reduced. CONCLUSIONS: These findings suggested that AS-IV has neuroprotective function in CIRI rats, and its molecular mechanism may depend on the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (PKB)/Akt signalling pathway activated by PPARγ. AS-IV could be an effective therapeutic drug candidate for CIRI treatment.

Evaluation of VEGF, BDNF, TRKB expression in oral epithelial dysplasia, oral verrucous carcinoma and oral squamous cell carcinoma and their role as prognostic indicator.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a serious health disease that can lead to a reduced quality of life or even death. It ranks sixth in terms of cancer expansion. It is one of India's primary causes of natural death. In OSCC such potentially malignant Disorders (PMDs) are precancerous lesions with such a high risk of progression. Tumor angiogenesis is a one of the basic biomarkers that may influence the proliferation of a precancerous lesion into the cancerous lesion. Tropomyosin receptor kinase B (TrkB), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) also play important roles in carcinogenesis by promoting angiogenesis. The construction of new vessels of blood from existing vasculature is referred as angiogenesis. AIM OF THE STUDY: To get deep insights of immunohistochemistry expression of VEGF, BDNF, and TRKB in oral epithelial dysplasia (OED), verrucous carcinoma (VC), and OSCC. MATERIAL AND METHODS: The study included 100 formalin-fixed paraffin-embedded tissue blocks from 20 cases of OED, 20 cases of VC, and 60 cases of OSCC [20 cases of well-differentiated oral squamous cell carcinoma (WD-OSCC), 20 cases of moderately differentiated oral squamous cell carcinoma (MD-OSCC), and 20 cases of poorly differentiated oral squamous cell carcinoma (PD-OSCC). The staining intensity and distribution of VEGF, BNDF, and TrkB were examined and statistically analyzed using analysis of variance (ANOVA), post hoc Bonferroni test, independent t-test, Pearson's Chi-square test, and Pearson's correlation coefficient test. RESULTS: The immunoexpression of VEGF, BDNF, and TrkB was found to be elevated in the order of OEDs, VC, and OSCC. The percentage of positive was highest in PD-OSCC, followed by MD-OSCC and WD-OSCC. CONCLUSION: Based on our findings, angiogenesis plays a significant role in tumor growth and metastasis. A substantial relationship was discovered between VEGF, BDNF, TrkB expression, and increases in vascularity throughout the transition from OEDs to VCs and OSCCs.

Overexpression of BDNF Suppresses the Epileptiform Activity in Cortical Neurons of Heterozygous Mice with a Transcription Factor Sip1 Deletion.

Since genetic mutations during brain development play a significant role in the genesis of epilepsy, and such genetically determined epilepsies are the most difficult to treat, there is a need to study the mechanisms of epilepsy development with deletions of various transcription factors. We utilized heterozygous mice (Sip1wt/fl) with a neuronal deletion of the transcription factor Sip1 (Smad interacting protein 1) in the cerebral cortex. These mice are characterized by cognitive impairment and are prone to epilepsy. It is known that the brain-derived neurotrophic factor (BDNF) has a neuroprotective effect in various neurodegenerative diseases. Therefore, we created and applied an adeno-associated construct carrying the BDNF sequence selectively in neurons. Using in vitro and in vivo research models, we were able to identify a key gen, the disruption of whose expression accompanies the deletion of Sip1 and contributes to hyperexcitation of neurons in the cerebral cortex. Overexpression of BDNF in cortical neurons eliminated epileptiform activity in neurons obtained from heterozygous Sip1 mice in a magnesium-free model of epileptiform activity (in vitro). Using PCR analysis, it was possible to identify correlations in the expression profile of genes encoding key proteins responsible for neurotransmission and neuronal survival. The effects of BDNF overexpression on the expression profiles of these genes were also revealed. Using BDNF overexpression in cortical neurons of heterozygous Sip1 mice, it was possible to achieve 100% survival in the pilocarpine model of epilepsy. At the level of gene expression in the cerebral cortex, patterns were established that may be involved in the protection of brain cells from epileptic seizures and the restoration of cognitive functions in mice with Sip1 deletion.

Behavioral and Amygdala Biochemical Damage Induced by Alternating Mild Stress and Ethanol Intoxication in Adolescent Rats: Reversal by Argan Oil Treatment?

Adolescence is a critical period when the effects of ethanol and stress exposure are particularly pronounced. Argan oil (AO), a natural vegetable oil known for its diverse pharmacological benefits, was investigated for its potential to mitigate addictive-like behaviors and brain damage induced by adolescent intermittent ethanol intoxication (IEI) and unpredictable mild stress (UMS). From P30 to P43, IEI rats received a daily ip ethanol (3 g/kg) on a two-day on/two-day off schedule. On alternate days, the rats were submitted to UMS protocol. Next, a two-bottle free access paradigm was performed over 10 weeks to assess intermittent 20% ethanol voluntary consumption. During the same period, the rats were gavaged daily with AO (15 mL/kg). Our results show that IEI/UMS significantly increased voluntary alcohol consumption (from 3.9 g/kg/24 h to 5.8 g/kg/24 h) and exacerbated withdrawal signs and relapse-like drinking in adulthood. Although AO treatment slightly reduced ethanol intake, it notably alleviated withdrawal signs during abstinence and relapse-like drinking in adulthood. AO's effects were associated with its modulation of the HPA axis (elevated serum corticosterone), restoration of amygdala oxidative balance, BDNF levels, and attenuation of neurodegeneration. These findings suggest that AO's neuroprotective properties could offer a potential therapeutic avenue for reducing ethanol/stress-induced brain damage and addiction. Further research is needed to explore its mechanisms and therapeutic potential in alcohol use disorders.

Regenerative potentials of bone marrow mesenchymal stem cells derived exosomes or its combination with zinc in recovery of degenerated circumvallate papilla following surgical bilateral transection of glossopharyngeal nerve in rats.

BACKGROUND: Taste buds' innervation is necessary to sustain their cell turnover, differentiated taste buds and nerve fibers in circumvallate papilla (CVP) disappear following glossopharyngeal nerve transection. Normally, taste buds recover to baseline number in about 70 days. Bone marrow stem cell (BM-MSC) derived exosomes or their combination with Zinc chloride are used to assess their potential to speed up the regeneration process of CVP following bilateral deafferentation. METHODS: Twenty-eight male Sprague-Dawley rats were randomly divided into four groups; Group I: subjected to sham operation followed by IP injection of saline. The other experimental groups (II, III and IV) were subjected to surgical bilateral transection of glossopharyngeal nerve. Group II received single IP injection of saline. Group III received single IV injection of BM-MSC-derived exosomes (100 µg). Group IV received single IV injection of BM-MSC-derived exosomes and single IP injection of zinc chloride (5 mg/kg). After 28 days, CVP was dissected and prepared for histological and histomorphometric analysis, RT-PCR for cytokeratin 8 gene expression, ELISA to assess protein level of brain-derived neurotrophic factor, redox state analysis of malondialdehyde and glutathione content, followed by statistical analysis. RESULTS: Histopathologically, group II exhibited great tissue damage with marked reduction in taste buds and signs of degeneration in the remaining ones. Group III was close to control group with marked improvement in taste buds' number and structure. Group IV showed inferior results when compared to group III, with many immature taste buds and signs of degeneration. Statistical results showed that groups I and III have significantly higher values than groups II and IV regarding taste buds' number, cytokeratin 8, and reduced glutathione. However, malondialdehyde demonstrated high significant values in group IV compared to groups I and III. Regarding brain-derived neurotrophic factor, group III had significantly higher values than group II. CONCLUSION: BM-MSC-derived exosomes have superior regenerative potentials in acceleration of CVP and nerve healing following bilateral transection of glossopharyngeal nerve in contrary to its combination with zinc chloride.

Myokines May Be the Answer to the Beneficial Immunomodulation of Tailored Exercise-A Narrative Review.

Exercise can regulate the immune function, activate the activity of immune cells, and promote the health of the organism, but the mechanism is not clear. Skeletal muscle is a secretory organ that secretes bioactive substances known as myokines. Exercise promotes skeletal muscle contraction and the expression of myokines including irisin, IL-6, BDNF, etc. Here, we review nine myokines that are regulated by exercise. These myokines have been shown to be associated with immune responses and to regulate the proliferation, differentiation, and maturation of immune cells and enhance their function, thereby serving to improve the health of the organism. The aim of this article is to review the effects of myokines on intrinsic and adaptive immunity and the important role that exercise plays in them. It provides a theoretical basis for exercise to promote health and provides a potential mechanism for the correlation between muscle factor expression and immunity, as well as the involvement of exercise in body immunity. It also provides the possibility to find a suitable exercise training program for immune system diseases.

Clinical Efficacy and Mechanistic Insights of Anshen Dingzhi Prescription on Breast Cancer-Related PTSD Through Network Pharmacology and Molecular Docking.

Anshen Dingzhi prescription (ADP) is a classic prescription of traditional Chinese medicine, which has been used in the treatment of neuropsychiatric diseases. However, its treatment of breast cancer-related post-traumatic stress disorder (BC-PTSD) lacks clinical research evidence and its mechanism is not clear. The present study investigated the efficacy and action mechanism of ADP against BC-PTSD. The results of the clinical trial showed that after 4 weeks of treatment, both groups showed reduced post-traumatic stress disorder checklist-civilian version (PCL-C), Pittsburgh sleep quality index (PSQI), self-rating depression scale (SDS) and self-rating anxiety scale (SAS) scores, and increased functional assessment of cancer therapy-breast (FACT-B) scores. The serum cortisol (CORT), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) levels were decreased and brain-derived neurotrophic factor (BDNF) level were increased, and the improvement of serum TNF-α, IL-1ß, and BDNF in treatment group was better than that of the control group. The overall treatment efficacy in the treatment group (43.90%) was superior to that in the control group (23.81%), and the overall incidence of adverse effects was lower than that in the control group. The results of network analysis and molecular docking showed that ADP blood components could act on IL1B, TNF, and BDNF. ADP contributes to the treatment of BC-PTSD symptoms, with a mechanism possibly related to its regulatory effect on TNF-α, IL-1ß, and BDNF levels.Trial registration: Chinese Clinical Trial Registry, http://www.chictr.org.cn,ChiCTR2300077801.

Late-onset major depressive disorder: exploring the therapeutic potential of enhancing cerebral brain-derived neurotrophic factor expression through targeted microRNA delivery.

Major depressive disorder (MDD) is a severe psychiatric condition that significantly impacts the overall quality of life. Although MDD can occur across all age groups, it is notably prevalent among older individuals, with the aggravating circumstance that the clinical condition is frequently overlooked and undertreated. Furthermore, older adults often encounter resistance to standard treatments, experience adverse events, and face challenges associated with polypharmacy. Given that late-life MDD is associated with heightened rates of disability and mortality, as well as imposing a significant economic and logistical burden on healthcare systems, it becomes imperative to explore novel therapeutic approaches. These could serve as either supplements to standard guidelines or alternatives for non-responsive patients, potentially enhancing the management of geriatric MDD patients. This review aims to delve into the potential of microRNAs targeting Brain-Derived Neurotrophic Factor (BDNF). In MDD, a significant decrease in both central and peripheral BDNF has been well-documented, raising implications for therapy response. Notably, BDNF appears to be a key player in the intricate interplay between microRNA-induced neuroplasticity deficits and neuroinflammation, both processes deeply implicated in the onset and progression of the disease. Special emphasis is placed on delivery methods, with a comprehensive comparison of the strengths and weaknesses of each proposed approach. Our hypothesis proposes that employing multiple microRNAs concurrently, with the ability to directly influence BDNF and activate closely associated pathways, may represent the most promising strategy. Regarding vehicles, although the perfect nanoparticle remains elusive, considering the trade-offs, liposomes emerge as the most suitable option.

Brain-Derived Neurotrophic Factor (BDNF) in the Frontal Cortex Enhances Social Interest in the BTBR Mouse Model of Autism.

A large body of evidence implies the involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of autism spectrum disorders (ASDs). A deficiency of BDNF in the hippocampus and frontal cortex of BTBR mice (a model of autism) has been noted in a number of studies. Earlier, we showed that induction of BDNF overexpression in the hippocampus of BTBR mice reduced anxiety and severity of stereotyped behavior, but did not affect social interest. Here, we induced BDNF overexpression in the frontal cortex neurons of BTBR mice using an adeno-associated viral vector, which resulted in a significant increase in the social interest in the three-chamber social test. At the same time, the stereotypy, exploratory behavior, anxiety-like behavior, and novel object recognition were not affected. Therefore, we have shown for the first time that the presence of BDNF in the frontal cortex is critical for the expression of social interest in BTBR mice, since compensation for its deficiency in this structure eliminated the autism-like deficiencies in the social behavior characteristic for these animals.

Cannabidiol Modulation of Nicotine-Induced Toxicity: Assessing Effects on Behavior, Brain-Derived Neurotrophic Factor, and Oxidative Stress in C57BL/6 Male Mice.

High doses of nicotine administered to rodents serve as a model for studying anxiety and test compounds' potential anxiolytic effects. At these doses, anxiety in rodents is accompanied by disruption of brain-derived neurotrophic factor (BDNF). The endocannabinoids and nicotine modulate several central nervous system processes via their specific receptors, impacting locomotion, anxiety, memory, nociception, and reward. Cannabidiol (CBD), an active ingredient of Cannabis sativa L., is devoid of psychoactive actions and has gained attention for its anxiolytic, antioxidant, and anti-inflammatory properties, among others. This work aims to examine the potential anxiety-reducing properties of CBD in a well-established experimental mouse model of anxiety-like behavior induced by high doses of nicotine on male C57BL/6 mice. In this context, the open-field behavioral test was specially conducted to assess CBD's effects on anxiety-like behavior and locomotion. Brain neuronal plasticity, modulated by BDNF, along with a diverse array of blood's metabolic markers, was examined as a means of evaluating systemic toxicity under various treatments. Finally, oxidative stress was evaluated through the measurement of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), while pro-inflammatory cytokine assessments were conducted to evaluate redox status and immune system function. Our research suggests that CBD shows potential in reducing anxiety-like behaviors induced by high doses of nicotine, by mitigating changes in BDNF protein levels in cerebral hemispheres and cerebellum. At the same time, CBD targets specific liver enzymes, maintains tissue's systemic toxicity (i.e., renal, kidney, and pancreatic), balances redox status (SOD, GSH, and MDA), and regulates the secretion of pro-inflammatory cytokines (TNF-alpha and IL-6).

Exploring the impact of acetylsalicylic acid and conditioned medium obtained from mesenchymal cells, individually and in combination, on cognitive function, histological changes, and oxidant-antioxidant balance in male rats with hippocampal injury.

BACKGROUND: The hippocampus is susceptible to damage, leading to negative impacts on cognition. Conditioned medium (CM) obtained from adipose tissue-derived mesenchymal stem cells (MSCs) and acetylsalicylic acid (ASA) have shown neuroprotective effects independently. This study explored the synergistic potential of ASA and CM from adipose-derived MSCs against hippocampal injury. METHODS: Adult male Wistar rats received bilateral hippocampal ethidium bromide (EB) injections to induce hippocampal damage. Rats were treated with ASA and/or CM derived from adipose tissue MSCs every 48 h for 16 days. Behavioral tests (open field test, Morris water maze, novel object recognition, and passive avoidance), oxidative stress, Western blot analysis of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) expression, and hippocampal histological investigation were conducted. RESULTS: Administration of EB caused impairments in spatial, recognition, and passive avoidance memory, as well as heightened oxidative stress, reduced BDNF/CDNF expression, and pyramidal cell loss in the hippocampal CA1 region. Administration of ASA, CM, or a combination of both mitigated these hippocampal damages and cognitive deficits, elevated BDNF and CDNF levels, and alleviated the CA1 necrosis caused by EB. Moreover, co-administering ASA and CM resulted in greater improvements in spatial memory compared to administering ASA alone, suggesting possible synergistic interactions. CONCLUSIONS: The ability of ASA, CM obtained from adipose tissue-derived MSCs, and their combination therapy to alleviate hippocampal injuries highlights their promising therapeutic potential as a neuroprotection strategy against brain damage. Our findings provide preliminary evidence of the potential synergistic effects of ASA and CM, which warrants further investigations.

Immune Cells Promote BDNF Expression by Infiltrated Macrophages via Interleukin 4 in the Cerebral Ischemia of Male Rats.

We reported that infiltrated Ly6C+ macrophages express brain-derived neurotrophic factor (BDNF) only at the cerebral cortex infarct in a rat dMCAO model. However, the changein neuron-expressed BDNF, the niche components that induce the Ly6C+ cells to express BDNF, and the cellular sources of these components, remain unclear. In this study, immunofluorescence double staining was performed to label BDNF and Ly6C on brain sections at 3, 24, and 48 h following distal middle cerebral artery occlusion (dMCAO) of male rats, and to stain BDNF with Ly6C, IL-4R, and IL-10R. A neutralizing anti-IL-4 antibody was injected into the infarct, and the IL-4 and BDNF concentrations in the subareas of the infarct were determined using enzyme-linked immunosorbent assay. To find out the cellular sources of IL-4, the markers for microglia, T cells, and neurons were co-stained with IL-4 separately. In certain infarct subareas, the main BDNF-expressing cells shifted quickly from NeuN+ neurons to Ly6C+ cells during 24-48 h post-stroke, and the Ly6C+/BDNF+ cells mostly expressed IL-4 receptor. Following IL-4 neutralizing antibody injection, the BDNF, IL-4 protein levels, and BDNF+/Ly6C+ cells decreased significantly. The main IL-4-expressing cell type in this infarct subarea is not neuron either, but immune cells, including microglia, monocyte, macrophages, and T cells. The neurons, maintained BDNF and IL-4 expression in the peri-infarct area. In conclusion, in a specific cerebral subarea of the rat dMCAO model, IL-4 secreted by immune cells is one of the main inducers for Ly6C+ cells to express BDNF.

New BDNF and NT-3 Cyclic Mimetics Concur with Copper to Activate Trophic Signaling Pathways as Potential Molecular Entities to Protect Old Brains from Neurodegeneration.

A low level of Neurotrophins (NTs), their Tyrosine Kinase Receptors (Trks), Vascular Endothelial Growth Factors (VEGFs) and their receptors, mainly VEGFR1 and VEGFR2, characterizes AD brains. The use of NTs and VEGFs as drugs presents different issues due to their low permeability of the blood-brain barrier, the poor pharmacokinetic profile, and the relevant side effects. To overcome these issues, different functional and structural NT mimics have been employed. Being aware that the N-terminus domain as the key domain of NTs for the binding selectivity and activation of Trks and the need to avoid or delay proteolysis, we herein report on the mimicking ability of two cyclic peptide encompassing the N-terminus of Brain Derived Growth Factor (BDNF), (c-[HSDPARRGELSV-]), cBDNF(1-12) and of Neurotrophin3 (NT3), (c-[YAEHKSHRGEYSV-]), cNT3(1-13). The two cyclic peptide features were characterized by a combined thermodynamic and spectroscopic approach (potentiometry, NMR, UV-vis and CD) that was extended to their copper(II) ion complexes. SH-SY5Y cell assays show that the Cu2+ present at the sub-micromolar level in the complete culture media affects the treatments with the two peptides. cBDNF(1-12) and cNT3(1-13) act as ionophores, induce neuronal differentiation and promote Trks and CREB phosphorylation in a copper dependent manner. Consistently, both peptide and Cu2+ stimulate BDNF and VEGF expression as well as VEGF release; cBDNF(1-12) and cNT3(1-13) induce the expression of Trks and VEGFRs.

Muscle-resident mesenchymal progenitors sense and repair peripheral nerve injury via the GDNF-BDNF axis.

Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal progenitors that can contribute to muscle tissue homeostasis and regeneration, as well as postnatal maturation and lifelong maintenance of the neuromuscular system. Recently, traumatic injury to the peripheral nerve was shown to activate FAPs, suggesting that FAPs can respond to nerve injury. However, questions of how FAPs can sense the anatomically distant peripheral nerve injury and whether FAPs can directly contribute to nerve regeneration remained unanswered. Here, utilizing single-cell transcriptomics and mouse models, we discovered that a subset of FAPs expressing GDNF receptors Ret and Gfra1 can respond to peripheral nerve injury by sensing GDNF secreted by Schwann cells. Upon GDNF sensing, this subset becomes activated and expresses Bdnf. FAP-specific inactivation of Bdnf (Prrx1Cre; Bdnffl/fl) resulted in delayed nerve regeneration owing to defective remyelination, indicating that GDNF-sensing FAPs play an important role in the remyelination process during peripheral nerve regeneration. In aged mice, significantly reduced Bdnf expression in FAPs was observed upon nerve injury, suggesting the clinical relevance of FAP-derived BDNF in the age-related delays in nerve regeneration. Collectively, our study revealed the previously unidentified role of FAPs in peripheral nerve regeneration, and the molecular mechanism behind FAPs' response to peripheral nerve injury.

MIND Diet Impact on Multiple Sclerosis Patients: Biochemical Changes after Nutritional Intervention.

There is substantial evidence supporting the neuroprotective effects of the MIND diet in neurodegenerative diseases like Parkinson's and Alzheimer's. Our aim was to evaluate the impact of a nutritional intervention (NI) with this diet on multiple sclerosis (MS) patients. The study was conducted in two stages. In the first stage, two groups were included: MS patients before the NI (group A) and healthy control subjects (group B). In this stage, groups (A) and (B) were compared (case-control study). In the second stage, group (A) was assessed after the NI, with comparisons made between baseline and final measurements (before-and-after study). In the case-control stage (baseline evaluation), we found significant differences in fatigue scores (p < 0.001), adherence to the MIND diet (p < 0.001), the serum levels of brain-derived neurotrophic factor (BDNF) (p < 0.001), and higher oxidative status in the MS group, with lower levels of reduced glutathione (p < 0.001), reduced/oxidised glutathione ratio (p < 0.001), and elevated levels of lipoperoxidation (p < 0.002) and 8-hydroxy-2'-deoxyguanosine (p < 0.025). The before-and-after intervention stage showed improvements in fatigue scores (p < 0.001) and physical quality-of-life scores (MSQOL-54) (p < 0.022), along with decreases in the serum levels of glial-derived neurotrophic factor (GDNF) (p < 0.041), lipoperoxidation (p < 0.046), and 8-hydroxy-2'-deoxyguanosine (p < 0.05). Consumption of the MIND diet is linked to clinical and biochemical improvement in MS patients.

NMC-4 Ameliorates Depression-Like Behavior and Neuroinflammation Caused by Chronic Unpredictable Mild Stress.

Depression is a prevalent mental disorder, but the side effects of antidepressants also make depressed patients resistant. Effective and safe antidepressants should be developed from traditional herbs, with the aim of reducing the side effects of antidepressants and improving the efficacy of drugs. In this study, the new macamide compound-4 (NMC-4) was synthesized for the first time, addressing the problem of difficult extraction, isolation, and low content of natural macamide. NMC-4 was characterized using mass spectrometry, nuclear magnetic resonance, and infrared spectroscopy. The protective effect of NMC-4 against cell injury was demonstrated to be stronger than that of natural macamide (N-benzylhexadecanamide, XA) using a PC12 cell injury model. The study explored the effects of NMC-4 on chronic unpredictable mild stress (CUMS)-induced depressive symptoms. NMC-4 significantly improved depressive-like behaviors. NMC-4 ameliorated CUMS-induced depressive-like behaviors by mitigating neuroinflammation and modulating the NF-κB/Nrf2 and BDNF/PI3K/Akt pathways.

Activity in the dorsal hippocampus-mPFC circuit modulates stress-coping strategies during inescapable stress.

Anatomical connectivity and lesion-deficit studies have shown that the dorsal and ventral hippocampi contribute to cognitive and emotional processes, respectively. However, the role of the dorsal hippocampus (dHP) in emotional or stress-related behaviors remains unclear. Here, we showed that neuronal activity in the dHP affects stress-coping behaviors in mice via excitatory projections to the medial prefrontal cortex (mPFC). The antidepressant ketamine rapidly induced c-Fos expression in both the dorsal and ventral hippocampi. The suppression of GABAergic transmission in the dHP-induced molecular changes similar to those induced by ketamine administration, including eukaryotic elongation factor 2 (eEF2) dephosphorylation, brain-derived neurotrophic factor (BDNF) elevation, and extracellular signal-regulated kinase (ERK) phosphorylation. These synaptic and molecular changes in the dHP induced a reduction in the immobility time of the mice in the tail-suspension and forced swim tests without affecting anxiety-related behavior. Conversely, pharmacological and chemogenetic potentiation of inhibitory neurotransmission in the dHP CA1 region induced passive coping behaviors during the tests. Transneuronal tracing and electrophysiology revealed monosynaptic excitatory connections between dHP CA1 neurons and mPFC neurons. Optogenetic stimulation of dHP CA1 neurons in freely behaving mice produced c-Fos induction and spike firing in the mPFC neurons. Chemogenetic activation of the dHP-recipient mPFC neurons reversed the passive coping behaviors induced by suppression of dHP CA1 neuronal activity. Collectively, these results indicate that neuronal activity in the dHP modulates stress-coping strategies to inescapable stress and contributes to the antidepressant effects of ketamine via the dHP-mPFC circuit.

Tannic acid: A possible therapeutic agent for hypermethioninemia-induced neurochemical changes in young rats.

This study explores the therapeutic benefits of tannic acid (TnA) in an experimental protocol of chronic hypermethioninemia in rats. Rats were categorized into four groups: Group I - control, Group II - TnA 30 mg/kg, Group III - methionine (Met) 0.2-0.4 g/kg + methionine sulfoxide (MS) 0.05-0.1 g/kg, Group IV - TnA/Met + MS. Saline was administered by subcutaneous pathway into groups I and II twice daily from postnatal day 6 (P6) to P28, whereas those in groups III and IV received Met + MS. From P28 to P35, groups II and IV received TnA orally. Animals from group III presented cognitive and memory impairment assessed through object recognition and Y-maze tests (p < 0.05). Elevated levels of reactive species, lipid peroxidation, and nitrites followed by a decline in sulfhydryl content, catalase activity, and superoxide dismutase activity were observed in animals treated with Met + MS (p < 0.05). However, TnA treatment reversed all these effects (p < 0.05). In group III, there was an increase in acetylcholinesterase activity and IL-6 levels, coupled with a reduction in Na+/K+-ATPase activity (p < 0.05). TnA was able to protect against these effects (p < 0.05). The gene expression of catalase, brain-derived neurotrophic factor, and nuclear factor erythroid 2-related factor 2 was decreased in the hippocampus and striatum from group III (p < 0.05). TnA reversed almost all of these alterations (p < 0.05). These findings suggest that TnA is a therapeutic target for patients with hypermethioninemia.

Intermittent fasting alerts neurotransmitters and oxidant/antioxidant status in the brain of rats.

Several recent studies have attempted to understand how fasting has benefits for body health, especially the nervous system. To evaluate the impact of intermittent fasting on body weight, brain neurotransmitters, brain oxidative stress, and brain-derived neurotrophic factor (BDNF) in several areas of the brain, this study was conducted in rats. Thirty male Wistar rats were randomly divided into two groups. Group 1 (15 rats) served as the control and group 2 (15 rats) underwent intermittent fasting (IF; 24 h) for 1, 7, or 15 days. The findings demonstrated that intermittent fasting significantly reduced body weight. In this sense, brain monoamines and amino acids, namely dopamine, glutamate, aspartate, and oxidative stress markers (malondialdehyde and nitric oxide), decreased significantly after 1 day of IF. However, norepinephrine, serotonin, gamma-amino butyric acid, and glycine increased significantly. Additionally, glutathione levels were markedly elevated in IF. Surprisingly, the neuromodulatory effect of intermittent fasting fluctuates depending on the IF period. To support this fluctuation, BDNF levels increased after 1 day in the hippocampus and decreased after 15 days of intermittent fasting in all areas of the brain tested. In conclusion, our results show that intermittent fasting has beneficial influences on the brain; however, prolonged intermittent fasting can also induce some unfavorable physiological outcomes that prevent optimal neurological function.

Upregulation of Phosphodiesterase 7A Contributes to Concurrent Pain and Depression via Inhibition of cAMP-PKA-CREB-BDNF Signaling and Neuroinflammation in the Hippocampus of Mice.

BACKGROUND: Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression. METHODS: C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior. RESULTS: This induction of chronic pain and depression in the 2 animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB, and p65. cAMP agonist forskolin reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice. CONCLUSIONS: Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling. Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression.