Semen Strychni Pulveratum and vomicine alleviate neuroinflammation in amyotrophic lateral sclerosis through cGAS-STING-TBK1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disorder characterized by the gradual deterioration of motor neurons. Semen Strychni pulveratum (SSP), a processed version of Semen Strychni (SS) powder, is widely used to treat ALS in China. Vomicine is one of the most primary components of SS. However, their pharmacological effects and mechanisms for ALS remain elusive. AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and anti-neuroinflammatory effects of SSP and vomicine, as well as to explore their protective roles in ALS and the underlying mechanisms. MATERIALS AND METHODS: In vivo, 8-week-old hSOD1-WT mice and hSOD1-G93A mice were orally administered different concentrations of SSP (SSP-L = 5.46 mg/ml, SSP-M = 10.92 mg/ml or SSP-H = 16.38 mg/ml) once every other day for 8 weeks. A series of experiments, including body weight measurement, footprint tests, Hematoxylin & Eosin staining, and Nissl staining, were performed to evaluate the preventive effect of SSP. Immunofluorescence staining, western blotting, and RT-qPCR were subsequently performed to evaluate activation of the cGAS-STING-TBK1 pathway in the spinal cord. In vitro, hSOD1G93A NSC-34 cells were treated with vomicine to further explore the pharmacological mechanism of vomicine in the treatment of ALS via the cGAS-STING-TBK1 pathway. RESULTS: SSP improved motor function, body weight loss, gastrocnemius muscle atrophy, and motor neuron loss in the spine and cortex of hSOD1-G93A mice. Furthermore, the cGAS-STING-TBK1 pathway was activated in the spinal cord of hSOD1-G93A mice, with activation predominantly observed in neurons and microglia. However, the levels of cGAS, STING, and pTBK1 proteins and cGAS, IRF3, IL-6, and IL-1ß mRNA were reversed following intervention with SSP. Vomicine not only downregulated the levels of cGAS, TBK1, IL-6 and IFN-ß mRNA, but also the levels of cGAS and STING protein in hSOD1G93A NSC-34 cells. CONCLUSION: This study demonstrated that SSP and vomicine exert neuroprotective and anti-neuroinflammatory effects in the treatment of ALS. SSP and vomicine may reduce neuroinflammation by regulating the cGAS-STING-TBK1 pathway, and could thereby play a role in ALS treatment.

Highly BBB-permeable nanomedicine reverses neuroapoptosis and neuroinflammation to treat Alzheimer's disease.

The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment.

The protective effects of chitosan and curcumin nanoparticles against the hydroxyapatite nanoparticles-induced neurotoxicity in rats.

Hydroxyapatite nanoparticles (HANPs) have extensive applications in biomedicine and tissue engineering. However, little information is known about their toxicity. Here, we aim to investigate the possible neurotoxicity of HANPs and the possible protective role of chitosan nanoparticles (CNPs) and curcumin nanoparticles (CUNPs) against this toxicity. In our study, HANPs significantly reduced the levels of neurotransmitters, including acetylcholine (Ach), dopamine (DA), serotonin (SER), epinephrine (EPI), and norepinephrine (NOR). HANPs significantly suppressed cortical expression of the genes controlling mitochondrial biogenesis such as peroxisome proliferator activator receptor gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (mTFA). Our findings revealed significant neuroinflammation associated with elevated apoptosis, lipid peroxidation, oxidative DNA damage and nitric oxide levels with significant decline in the antioxidant enzymes activities and glutathione (GSH) levels in HANPs-exposed rats. Meanwhile, co-supplementation of HANP-rats with CNPs and/or CUNPs significantly showed improvement in levels of neurotransmitters, mitochondrial biogenesis, oxidative stress, DNA damage, and neuroinflammation. The co-supplementation with both CNPs and CUNPs was more effective to ameliorate HANPs-induced neurotoxicity than each one alone. So, CNPs and CUNPs could be promising protective agents for prevention of HANPs-induced neurotoxicity.

Recent advancement in understanding of Alzheimer's disease: Risk factors, subtypes, and drug targets and potential therapeutics.

Alzheimer's disease (AD) is a significant neocortical degenerative disorder characterized by the progressive loss of neurons and secondary alterations in white matter tracts. Understanding the risk factors and mechanisms underlying AD is crucial for developing effective treatments. The risk factors associated with AD encompass a wide range of variables, including gender differences, family history, and genetic predispositions. Additionally, environmental factors such as air pollution and lifestyle-related conditions like cardiovascular disease, gut pathogens, and liver pathology contribute substantially to the development and progression of AD and its subtypes. This review provides current update and deeper insights into the role of diverse risk factors, categorizing AD into its distinct subtypes and elucidating their specific pathophysiological mechanisms. Unlike previous studies that often focus on isolated aspects of AD, our review integrates these factors to offer a comprehensive understanding of the disease. Furthermore, the review explores a variety of drug targets linked to the neuropathology of different AD subtypes, highlighting the potential for targeted therapeutic interventions. We further discussed the novel therapeutic options and categorized them according to their targets. The roles of different drug targets were comprehensively studied, and the mechanism of action of their inhibitors was discussed in detail. By comprehensively covering the interplay of risk factors, subtype differentiation, and drug targets, this review provides a deeper understanding of AD and suggests directions for future research and therapeutic strategies.

The effect of Brucella abortus on glial activation and cell death in adult male rat's hippocampus.

A zoonotic disease called brucellosis can cause flu-like symptoms and heart inflammation. The bacteria responsible for this disease can also enter the brain, causing a condition called neurobrucellosis that can result in long-term neurological problems. In this study, researchers aimed to determine the changes in the hippocampal cells of rats infected with Brucella. For the study, 24 adult male albino rats were inoculated with 1 × 106 CFU Brucella abortus 544. The rats were then deeply anesthetized, and their hippocampus samples were taken for stereological, histological, and molecular studies. The results showed that the infected rats had increased microgliosis and astrogliosis. Furthermore, a high level of caspase-3 in their hippocampal tissue indicated their susceptibility to apoptosis. Additionally, there was a decrease in expression of Ki67, which further supported this. Sholl's analysis confirmed a significant failure in glial morphology. The study demonstrated that the pathogen has the ability to destroy the hippocampus and potentially affect its normal physiology. However, more research is needed to clarify various aspects of neurobrucellosis.

rTMS mechanisms for posttraumatic stress disorder treatment in a mouse model.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a psychiatric disease that may follow traumatic exposure. Current treatments fail in about 30% of patients. Although repeated transcranial magnetic stimulation (rTMS) applied to the prefrontal cortex has been shown to be effective in the treatment of PTSD, the mechanisms need further investigation. OBJECTIVE: Using a PTSD animal model, we verify the beneficial effect of rTMS, and explore the changes it induces on two putative PTSD mechanisms, GABA/glutamate neurotransmission and neuroinflammation. METHODS: PTSD-like symptoms were elicited in twenty-six mice using a foot-shock conditioning procedure. Fourteen of the 26 were then treated using rTMS (12 were untreated). In the control group (n = 30), 18 were treated with rTMS and 12 were untreated. Animals were sacrificed after re-exposure. The infralimbic (IL) cortex, basolateral amygdala (BLA) and ventral CA1 (vCA1) were isolated using laser microdissection. mRNA was then investigated using PCR array analysis targeting GABA/glutamate and inflammatory pathways. RESULTS: The rTMS treatment significantly decreased the contextual fear memory phenotype. These changes were associated with reduced mRNA expression related to inflammation in the IL cortex and the vCA1, and lowered mRNA-related glutamate neurotransmission and increased GABA neurotransmission in the BLA. CONCLUSION: Our results suggest that our rTMS treatment was associated with local anti-inflammatory effects and limbic effects, which seemed to counteract PTSD effects. Several of these changes (both stress- and rTMS-induced) have implications for the drug sensitivity of limbic brain areas, and may help in the design of future therapeutic protocols.

Activity-based anorexia (ABA) model: Effects on brain neuroinflammation, redox balance and neuroplasticity during the acute phase.

Several evidences suggest that immuno-inflammatory responses are involved in the pathogenesis of anorexia nervosa (AN). Herein we investigate the possible alteration of key mediators of inflammation, redox balance, and neuroplasticity in the brain of rats showing an anorexic-like phenotype. We modeled AN in adolescent female rats using the activity-based anorexia (ABA) paradigm and measured gene expression levels of targets of interest in the prefrontal cortex (PFC) and dorsal hippocampus (DH). We observed reduced mRNA levels of pro-inflammatory cytokines IL-1ß and TNF-α, the inflammasome NLRP3, and the microglial marker CD11b in both PFC and DH of ABA animals. Conversely, the mRNA of IL-6, which acts as both a pro-inflammatory and anti-inflammatory cytokine, was increased. Moreover, we observed an overall upregulation of different antioxidant enzymes in PFC, while their profile was not affected or opposite in the DH, with the exception of MT1α. Interestingly, ABA animals showed elevated levels of the neuroplasticity marker BDNF in both PFC and DH. Our data indicate that ABA induction is associated with anatomical-specific cerebral alteration of mediators of neuroinflammation, oxidative balance and neuroplasticity. Although more research should be conducted, these results add important information about the role of these systems in the complex AN etiopathogenesis.

TNFR2 signaling in oligodendrocyte precursor cells suppresses their immune-inflammatory function and detrimental microglia activation in CNS demyelinating disease.

Multiple Sclerosis (MS) is a chronic degenerative disease of the central nervous system (CNS) characterized by inflammation, demyelination, and progressive neurodegeneration. These processes, combined with the failure of reparative remyelination initiated by oligodendrocyte precursor cells (OPCs), lead to irreversible neurological impairment. The cytokine tumor necrosis factor (TNF) has been implicated in CNS repair via activation of its cognate receptor TNFR2 in glia. Here, we demonstrate the important role of TNFR2 in regulating OPC function in vivo during demyelinating disease, and that TNFR2 expressed in OPCs modulates OPC-microglia interactions. In PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp mice with selective TNFR2 ablation in OPCs, we observed an earlier onset and disease peak in experimental autoimmune encephalomyelitis (EAE). This was associated with accelerated immune cell infiltration and increased microglia activation in the spinal cord. Similarly, PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp mice showed rapid and increased microglia reactivity compared to control mice in the corpus callosum after cuprizone-induced demyelination, followed by chronic reduction in the number of mature myelinating oligodendrocytes (OLs). With EAE and cuprizone models combined, we uncovered that TNFR2 does not have a cell autonomous role in OPC differentiation, but may be important for survival of newly formed mature OLs. Finally, using an in vitro approach, we demonstrated that factors released by Tnfrsf1b ablated OPCs drove microglia to develop an exacerbated "foamy" phenotype when incubated with myelin-rich spinal cord homogenate, aberrantly increasing lysosomal lipid accumulation. Together, our data indicate that TNFR2 signaling in OPCs is protective by dampening their immune-inflammatory activation and by suppressing neurotoxic microglia reactivity. This suggests that boosting TNFR2 activation or its downstream cascades could be an effective strategy to restore OPC reparative capacity in neuroimmune and demyelinating disease.

Research progress in the mechanisms and functions of specialized pro-resolving mediators in neurological diseases.

The nervous system interacts with the immune system through a variety of cellular regulators, signaling pathways, and molecular mechanisms. Disruptions in these interactions lead to the development of multiple neurological diseases. Recent studies have identified that specialized pro-resolving mediators (SPMs) play a regulatory role in the neuroimmune system. This study reviews recent research on the function of SPMs in the inflammatory process and their association with the nervous system. The review aims to provide new perspectives for studying the pathogenesis of neurological diseases and identify novel targets for clinical therapy.

Advancing Alzheimer's Research With Zebrafish Models: Current Insights, Addressing Challenges, and Charting Future Courses.

Alzheimer's disease (AD) is a neurological condition that progressively impairs cognitive function and results in memory loss. Despite substantial research efforts, little is known about the specific processes driving AD, and there are few proven therapies. Because of their physiological and genetic resemblance to humans, zebrafish (Danio rerio) have become an important model organism for furthering research on AD. This abstract discusses the difficulties faced, looks at the insights currently garnered from zebrafish models, and suggests future research options. AD knowledge has greatly benefited from the use of zebrafish models. Transgenic zebrafish that express human AD-associated genes, such as tau and amyloid precursor protein (APP), display tau neurofibrillary tangles (NFTs) and amyloid-beta (Aß) plaques, two of the disease's main clinical characteristics. These models have clarified the roles of oxidative stress, inflammation, and calcium homeostasis in the course of AD and allowed for the purpose of high-throughput screening of potential therapeutic agents. Understanding the growth and deterioration of neurons has been greatly aided by real-time zebrafish imaging. Fully using zebrafish models in AD research requires addressing a number of issues. The dissimilarities in zebrafish anatomy and physiology from humans, the difficulty of developing models that replicate progressive and late-onset AD (LOAD), and the requirement for standardized procedures to evaluate alterations in zebrafish cognition and behavior are a few issues. Furthermore, variations in the genetic makeup of zebrafish strains might affect the results of experiments. Future directions include developing standardized behavioral assays and cognitive tests, working together to create extensive databases of zebrafish genetic and phenotypic data, and using genetic engineering techniques like CRISPR/Cas9 to create more complex zebrafish models. Combining zebrafish models with other model species helps expedite the conversion of research results into therapeutic applications and offers a more thorough knowledge of AD. To sum up, zebrafish models have made a substantial contribution to Alzheimer's research by offering insightful information on the causes of the illness and possible therapies. By tackling present issues and formulating a planned future path, we can improve the use of zebrafish to decipher the mysteries of Alzheimer's and help create successful treatments.

Neuropathology and neuroinflammation in Alzheimer's disease via bidirectional lung-brain axis.

Alzheimer's disease (AD) is the most common form of age-related dementia worldwide. Although the neuropathology of AD is clear, its pathogenesis remains unclear. Recently, conceptualising AD as brain-centred has reoriented many scientists because the close functional relationship between the peripheral and central nerves is increasingly recognised. Recently, various studies have focused on the crosstalk between peripherals and centrals. A new hotspot of research and new therapeutic strategies have emerged from this great progress. This mini-review is an overview of the potential molecular mechanism in AD via the bidirectional lung-brain axis, providing a new perspective for the systemic understanding of AD onset.

Melatonin rescues pregnant female mice and their juvenile offspring from high fat diet-induced alzheimer disease neuropathy.

High fat diet (HFD) is a prime factor, which contributes to the present epidemic of metabolic syndrome. Prolonged intake of HFD induces oxidative stress (OS) that in turn causes neuroinflammation, neurodegeneration, insulin resistance, amyloid burden, synaptic dysfunction and cognitive impairment hence leading to Alzheimer's disease neuropathy. Melatonin (secreted by the Pineal gland) has the potential to nullify the toxic effects of reactive oxygen species (ROS) and have been shown to ameliorate various complications induced by HFD in rodent models. This study aimed to assess the neurotherapeutic effects of melatonin on HFD-induced neuroinflammation and neurodegeneration mediated by OS in pregnant female mice and their offspring. Western blotting, immunohistochemistry and antioxidant enzyme assays were used for quantification of samples from the hippocampal region of the brain of pregnant albino mice and their offspring. Short- and long-term memory was assessed by Y-maze and Morris Water Maze tests. HFD significantly induced OS leading to AD like neuropathology in the pregnant mice and their offspring while melatonin administration simultaneously with the HFD significantly prevented this neuropathy. This study reports that melatonin exerts these effects through the stimulation of SIRT1/Nrf2/HO-1 pathway that in turn reduces the HFD-induced OS and its downstream signaling. In conclusion melatonin prevents HFD-induced multiple complications that ultimately leads to the memory dysfunction in pregnant female mice and their successive generation via activation of SIRT1/Nrf2 signaling pathway.

Inflammation and heterogeneity in synucleinopathies.

Neurodegenerative diseases represent a huge healthcare challenge which is predicted to increase with an aging population. Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), present complex challenges in understanding their onset and progression. They are characterized by the abnormal aggregation of α-synuclein in the brain leading to neurodegeneration. Accumulating evidence supports the existence of distinct subtypes based on the site of α-synuclein aggregation initiation, genetics, and, more recently, neuroinflammation. Mediated by both central nervous system-resident cells, peripheral immune cells, and gut dysbiosis, neuroinflammation appears as a key process in the onset and progression of neuronal loss. Sex-based differences add another layer of complexity to synucleinopathies, influencing disease prevalence - with a known higher incidence of PD in males compared to females - as well as phenotype and immune responses. Biological sex affects neuroinflammatory pathways and the immune response, suggesting the need for sex-specific therapeutic strategies and biomarker identification. Here, we review the heterogeneity of synucleinopathies, describing the etiology, the mechanisms by which the inflammatory processes contribute to the pathology, and the consideration of sex-based differences to highlight the need for personalized therapeutics.

KIT-13, a novel plasmalogen derivative, attenuates neuroinflammation and amplifies cognition.

Plasmalogens (Pls) are specialized phospholipids integral to brain health, whose decline due to aging and stress contributes to cognitive impairment and neuroinflammation. This study explores the potential of a novel Pls derivative, KIT-13 (1-O-octadecyl-2-arachidonoyl-sn-glycerol-3-phosphoethanolamine), in mitigating neuroinflammation and enhancing cognition. When administered to mice, KIT-13 exhibited potent memory enhancement attributed to upregulated brain-derived neurotrophic factor (BDNF), a key player in cognitive processes. In vitro experiments with neuronal cells revealed KIT-13's ability to induce robust cellular signaling, surpassing natural plasmalogens. KIT-13 also promoted neurogenesis and inhibited apoptosis of neuronal-like cells, highlighting its potential in fostering neuronal growth and plasticity. Additionally, KIT-13 treatments reduced pro-inflammatory cytokine expression and attenuated glial activation in the brain. KIT-13's superior efficacy over natural Pls positions it as a promising therapeutic candidate for neurodegenerative conditions such as Alzheimer's disease, characterized by cognitive decline and neuroinflammation. This study presents KIT-13 as an innovative approach for addressing cognitive impairment and neuroinflammatory pathologies.

A Review of the Retinal Impact of Traumatic Brain Injury and Alzheimer's Disease: Exploring Inflammasome Complexes and Nerve Fiber Layer Alterations.

A huge number of new cases - around a few million of traumatic brain injury (TBI) - are recorded globally each year, making it a major public health risk. A significant portion of all accident-related deaths are attributable to TBI, a notable mortality rate. There are TBI deaths in every age range. Long-term neurobehavioral impacts, such as altered emotions and personalities, cognitive and mental deficits, and so on, are experienced by the majority of survivors. Our main objective is to understand the possible mechanism of the NLRP3 inflammasome in retinal neurons and enhance precision regarding reducing the burden of retinal neurodegeneration in TBI-induced AD. Both primary and secondary insults initiate the intricate pathophysiology of traumatic brain injury. Primary injuries are caused by mechanical force and occur right after the collision. Long-lasting and delayed secondary injuries follow. Studies demonstrating the continuous nature of research on the relationship between retinal neurons and TBI-induced Alzheimer's disease (AD) include neurodegeneration, retinal changes, and inflammatory response biomarkers. TBI can cause changes that resemble those seen in AD. This includes the accumulation of tau tangles and amyloid-beta plaques, which are also observed in the retina and imply a potential relationship between AD, traumatic brain injury, and retinal health. The linkage between TBI and AD, the effect of the innate immune system in post-TBI AD, the function of immunological moderators, the activation and assembly of inflammasomes in TBI, the pathophysiology of TBI, and the connection between TBI and inflammasome activity were the main topics of discussion in the following discussions. Of particular interest was the potential mechanism by which the NLRP3 inflammasome, in conjunction with SREBP2 and SCAP inflammasome, in retinal neurons in TBI-induced AD. The thinning of RNFL, poor lipid metabolism, and new developments such as drug delivery technologies, lipid metabolism modulation in retinal neurons, and drug-targeting lipid pathways and their mechanisms are then covered in this article.

Probiotics-role in alleviating the impact of alcohol liver disease and alcohol deaddiction: a systematic review.

Background: There are few efficient treatment options for alcohol addiction, which continues to be a serious public health concern. The possible contribution of gut microbiota to the onset and progression of alcohol addiction has been brought to light by recent studies. Probiotics have become a cutting-edge intervention in the treatment of alcohol consumption disorder because of its favorable effects on gut health. The purpose of this systematic review is to assess the body of research on the advantages of probiotics in treating alcoholism and associated neuroinflammatory conditions. Methods: To find pertinent research published from January 2012 to 2023, a thorough search of electronic databases, including PubMed, Scopus, Google Scholar and Web of Science, was carried out. Included were studies looking at how probiotics affect neuroinflammation, gut- brain axis regulation, alcohol addiction, and related behaviors. Findings: Several investigations have shown how beneficial probiotics are in reducing systemic inflammation and alcoholic liver disease (ALD). Probiotic treatments successfully corrected the imbalance of microbiota, decreased intestinal permeability, and stopped the passage of bacterial constituents such lipopolysaccharides (LPS) into the bloodstream. Additionally, probiotics helped to regulate neurotransmitter pathways, especially those connected to GABA, glutamate, and dopamine, which are intimately linked to behaviors related to addiction. Furthermore, it was shown that probiotics altered the expression of neurotransmitter signaling and dopamine receptors. Conclusion: There is strong evidence from this systematic study that probiotics have potential advantages in treating alcohol addiction. The potential of probiotic therapies is demonstrated by the way they modulate important neurotransmitter pathways implicated in addiction, decrease neuroinflammation, and restore the balance of gut flora. To fully investigate the therapeutic potential of probiotics in treating alcohol addiction and enhancing the general wellbeing of those afflicted by this condition, more research is necessary.

Colchicine treatment in amyotrophic lateral sclerosis: safety, biological and clinical effects in a randomized clinical trial.

In preclinical studies, the anti-inflammatory drug colchicine, which has never been tested in amyotrophic lateral sclerosis, enhanced the expression of autophagy factors and inhibited accumulation of transactive response DNA-binding protein 43 kDa, a known histopathological marker of amyotrophic lateral sclerosis. This multicentre, randomized, double-blind trial enrolled patients with probable or definite amyotrophic lateral sclerosis who experienced symptom onset within the past 18 months. Patients were randomly assigned in a 1:1:1 ratio to receive colchicine at a dose of 0.005 mg/kg/day, 0.01 mg/kg/day or placebo for a treatment period of 30 weeks. The number of positive responders, defined as patients with a decrease lesser than 4 points in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score during the 30-week treatment period, was the primary outcome. Disease progression, survival, safety and quality of life at the end of treatment were the secondary clinical outcomes. Secondary biological outcomes included changes from baseline to treatment end of stress granule and autophagy responses, transactive response DNA-binding protein 43 kDa, neurofilament accumulation and extracellular vesicle secretion, between the colchicine and placebo groups. Fifty-four patients were randomized to receive colchicine (n = 18 for each colchicine arm) or placebo (n = 18). The number of positive responders did not differ between the placebo and colchicine groups: 2 out of 18 patients (11.1%) in the placebo group, 5 out of 18 patients (27.8%) in the colchicine 0.005 mg/kg/day group (odds ratio = 3.1, 97.5% confidence interval 0.4-37.2, P = 0.22) and 1 out of 18 patients (5.6%) in the colchicine 0.01 mg/kg/day group (odds ratio = 0.5, 97.5% confidence interval 0.01-10.2, P = 0.55). During treatment, a slower Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised decline was detected in patients receiving colchicine 0.005 mg/kg/day (mean difference = 0.53, 97.5% confidence interval 0.07-0.99, P = 0.011). Eight patients experienced adverse events in placebo arm (44.4%), three in colchicine 0.005 mg/kg/day (16.7%) and seven in colchicine 0.01 mg/kg/day arm (35.9%). The differences in adverse events were not statistically significant. In conclusion, colchicine treatment was safe for amyotrophic lateral sclerosis patients. Further studies are required to better understand mechanisms of action and clinical effects of colchicine in this condition.

Curcumin attenuated neuroinflammation via the TLR4/MyD88/NF-κB signaling way in the juvenile rat hippocampus following kainic acid-induced epileptic seizures.

The study examined curcumin's impart on relieving neuroinflammation of juvenile rats in kainic acid (KA) induced epileptic seizures by inhibiting the TLR4/MyD88/NF-κB pathway. There were five groups: control, KA, KA + curcumin (KC), KA + oxcarbazepine (OXC) (KO), KA + curcumin + OXC (KCO) groups. KA was stereotactically injected into right hippocampus following intraperitoneal injection of curcumin or (and) OXC for seven days. The rats in the above groups were randomly divided into three subgroups (at 6 h, 24 h, and 72 h of KA administration) following the seizure degree assessed. The number of NeuN (+) neurons and GFAP (+) astrocytes was counted. The gene and protein levels of TLR4, MyD88, and NF-κB were detected. Compared with the KA group, the seizure latency was longer, and the incidence of status epilepticus (SE) was lower in the KC, KO, and KCO groups. The most significant changes were in the KCO group. At 72 h following KA injected, the number of neurons was the least, and the number of astrocytes was the most in the KA group. The number of neurons was the most and the number of astrocytes was the least in the KCO group. At 24 h, the mRNA and protein levels of TLR4, MyD88, and NF-κB in the KA group were the most. The above valves were the least in the KCO group. Therefore, curcumin could enhance anti-epileptic effect of OXC, protect injured neurons and reduce proliferated glial cells of the hippocampus of epileptic rats by inhibiting inflammation via the TLR4/MyD88/NF-κB pathway.

Gas6/Axl signaling promotes hematoma resolution and motivates protective microglial responses after intracerebral hemorrhage in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) stands out as the most fatal subtype of stroke, currently devoid of effective therapy. Recent research underscores the significance of Axl and its ligand growth arrest-specific 6 (Gas6) in normal brain function and a spectrum of neurological disorders, including ICH. This study is designed to delve into the role of Gas6/Axl signaling in facilitating hematoma clearance and neuroinflammation resolution following ICH. METHODS: Adult male C57BL/6 mice were randomly assigned to sham and ICH groups. ICH was induced by intrastriatal injection of autologous arterial blood. Recombinant mouse Gas6 (rmGas6) was administered intracerebroventricularly 30 min after ICH. Virus-induced knockdown of Axl or R428 (a selective inhibitor of Axl) treatment was administrated before ICH induction to investigate the protective mechanisms. Molecular changes were assessed using western blot, enzyme-linked immunosorbent assay and immunohistochemistry. Coronal brain slices, brain water content and neurobehavioral tests were employed to evaluate histological and neurofunctional outcomes, respectively. Primary glia cultures and erythrophagocytosis assays were applied for mechanistic studies. RESULTS: The expression of Axl increased at 12 h after ICH, peaking on day 3. Gas6 expression did not remarkably changed until day 3 post-ICH. Early administration of rmGas6 following ICH significantly reduced hematoma volume, mitigated brain edema, and restored neurological function. Both Axl-knockdown and Axl inhibitor treatment abolished the neuroprotection of exogenous Gas6 in ICH. In vitro studies demonstrated that microglia exhibited higher capacity for phagocytosing eryptotic erythrocytes compared to normal erythrocytes, a process reversed by blocking the externalized phosphatidylserine on eryptotic erythrocytes. The erythrophagocytosis by microglia was Axl-mediated and Gas6-dependent. Augmentation of Gas6/Axl signaling attenuated neuroinflammation and drove microglia towards pro-resolving phenotype. CONCLUSIONS: This study demonstrated the beneficial effects of recombinant Gas6 on hematoma resolution, alleviation of neuroinflammation, and neurofunctional recovery in an animal model of ICH. These effects were primarily mediated by the phagocytotic role of Axl expressed on microglia.

Therapeutic Effects of Alpha Lipoic Acid and/or Caffeine-Loaded Chitosan Nanoparticles on Memory Impairment and Neurochemical Changes in High-Fat Diet-Induced Obese Rats.

The therapeutic effects of alpha lipoic acid (LA) and/or caffeine-loaded chitosan nanoparticles (CCNPs) on obesity-induced memory impairment were evaluated in the present study. Rats were divided into control rats, obese rats induced by high fat diet (HFD) and obese rats treated with LA and/or CCNPs. Obesity was confirmed by measuring the body mass index (BMI). Memory and cognitive functions were evaluated by novel object recognition test (NORT). The levels of serotonin (5-HT), dopamine (DA), norepinephrine (NE), lipid peroxidation (MDA), nitric oxide (NO), reduced glutathione (GSH), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), leptin (LEP) and ghrelin (GHR) and the activities of monoamine oxidase (MAO), acetylcholinesterase (AchE) and Na+,K+,ATPase were determined in the cortex and hippocampus. The cerebral histopathological alterations were examined in obese rats. Obese rats showed impaired memory and exhibited significant neurochemical changes, including decreased levels of 5-HT, DA, GSH, GHR, and Na+,K+-ATPase activity, as well as an increase in AchE, MAO, MDA, NO, IL-1ß, TNF-α, and LEP. LA and/or CCNPs treatment reduced BMI and improved memory. LA or CCNPs alleviated the cortical and hippocampal neurochemical changes and histopathological changes induced by obesity. Furthermore, LA and CCNPs exhibited antioxidant and anti-inflammatory properties, which likely contributed to their effects. However, no synergistic effect was observed between LA and CCNPs. These findings suggest that LA or CCNPs may be a potential therapy against obesity and its adverse effects on memory, mediated by their ability to restore monoamine levels and exhibit antioxidant and anti-inflammatory properties.