Neuroprotective Effects Research Articles

The effect of Amantadine on recovery, postoperative cognitive dysfunction and pain after propofol anesthesia in mice

IntroductionPostoperative cognitive dysfunction (POCD) encompasses a spectrum of cognitive impairments following surgery, attributed to disruptions in brain homeostasis. The pathogenesis involves glutamate toxicity, GABA receptor dysfunction, and alterations in NMDA and AMPA receptors. This study aimed to investigate the impact of pre-anesthetic amantadine administration on postoperative recovery time, POCD, and stress-related pain levels when combined with propofol anesthesia. MethodsTwenty-four adult male BALB/C mice were divided into four groups: Control, Propofol, Amantadine, and Amantadine+Propofol. Amantadine and propofol doses were administered intraperitoneally based on previous literature. Recovery time, pain levels (assessed via tail pinch and hot plate tests), cognitive functions (evaluated through Morris Water Maze), and locomotor activity (measured via Open Field Test) were recorded. ResultsAmantadine administration significantly reduced recovery time from propofol anesthesia, prolonged pain perception, and preserved cognitive functions compared to propofol alone. The time spent in the target quadrant in the Morris Water Maze was significantly longer in groups receiving amantadine. Additionally, the distance covered until finding the platform was significantly shorter in the propofol-only group. DiscussionAmantadine's neuroprotective effects, attributed to its antagonistic action on glutamate and NMDA receptors, mitigate the detrimental effects of propofol on cognitive function and pain perception. This study highlights the potential of combining amantadine with propofol to enhance postoperative outcomes. ConclusionAmantadine administration before propofol anesthesia positively influenced postoperative recovery, cognitive function preservation, and stress-related pain perception in mice. These findings suggest a potential therapeutic strategy to mitigate POCD and pain associated with surgery.

Therapeutic overview of sudachitin.

Citrus fruits are extensively cultivated and eaten both raw and in refined forms. Citrus fruit peels are highly concentrated in polyphenolic substances. This makes them useful resources. Polymethoxyflavones (PMFs), found in citrus peels, belong to a specific subclass of flavonoids where most or all hydroxyl groups are methylated. PMFs have been documented to possess chemopreventive actions, anticancer, anti-inflammatory, and anti-atherosclerosis properties, as well as neuroprotective effects. Sudachitin, a PMF, is primarily found in Citrus sudachi. Japan's Tokushima prefecture is home to this famous fruit. In recent years, there has been a growing interest among researchers in exploring the potential health benefits of sudachitin, spurred by its presence in traditional diets and its association with various positive health outcomes. Studies conducted over the past decade have revealed promising effects of sudachitin in multiple health conditions, including cancer, skin disorders, inflammatory conditions, diabetes, obesity, and neurodegenerative disorders. Although these promising results exist, there is still a need for thorough preclinical and clinical research to confirm sudachitin's effectiveness in treating chronic conditions. This review seeks to summarize animal and cell studies exploring sudachitin's pharmacological properties and the potential molecular pathways underlying its therapeutic effects. Through this, we aim to clarify the clinical potential of sudachitin across various disorders, paving the way for future research and the development of sudachitin-based therapies.

Selected Interleukins Relevant to Multiple Sclerosis: New Directions, Potential Targets and Therapeutic Perspectives.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that progresses with demyelination and neurodegeneration. To date, many studies have revealed the key role of interleukins in the pathogenesis of MS, but their impact has not been fully explained. The aim of the present study was to collect and review the results obtained so far regarding the influence of interleukins on the development and course of MS and to assess the potential for their further use. Through the platform "PubMed", terms related to interleukins and MS were searched. The following interval was set as the time criterion: 2014-2024. A total of 12,731 articles were found, and 100 papers were subsequently used. Cells that produce IL-10 have a neuroprotective effect, whereas those that synthesize IL-6 most likely exacerbate neuroinflammation. IL-12, IL-23 and IL-18 represent pro-inflammatory cytokines. It was found that treatment with an anti-IL-12p40 monoclonal antibody in a study group of MS patients showed a beneficial effect. IL-4 is a pleiotropic cytokine that plays a significant role in type 2 immune responses and inhibits MS progression. IL-13 is an anti-inflammatory cytokine through which the processes of oligodendrogenesis and remyelination occur more efficiently. The group of interleukins discussed in our paper may represent a promising starting point for further research aimed at finding new therapies and prognostic markers for MS.

Some Applications of Hericium erinaceus Mushrooms: A Review

The Lion's Mane mushroom, which has the scientific name Hericium erinaceus, can be defined as a medicinal fungus type. For very long time, it has been utilized in the conventional medicine in Asia for a variety of purposes. In the past few years, there had been a great deal of interest directed towards potential benefits to the health, which could be provided by this unique type of mushroom in particular, when it comes to the treatment of various diseases. The concentration will be focused on examining the way that Hericium erinaceus as well as its bioactive elements could be utilized for therapeutic purposes within the area od disease control. This review states the possible Hericium erinaceus advantages in cases that are related to some health issues, such as metabolic problems, gastrointestinal diseases, neurodegenerative disorders, and immune system problems. In addition to that, the present paper discusses the work that is used for providing the therapeutic effects. It is stated that some of the characteristics of the Hericium erinaceus include having anti-inflammatory, neuro-protective, anti-oxidant, and immune-modulatory effects. Even though more studies are needed for detailed understanding of all the mechanisms that are involved in its activities, presenting evidences that strongly suggest possible Hericium erinaceus uses as one of the natural cures for a variety of illnesses, it is known as well in some cases as lion's mane mushroom, which fungus type that comes with extensive history and many potential advantages. As a result of its distinctive morphology, including bio-active compounds, in addition to its conventional uses have combined to the generation of much interest in a variety of areas. More research is needed for full understanding of the way that it works for the therapeutic applications and its potential implementations in the area of nutrition, cooking, and medicine. The cultivation of Hericium erinaceus might be viewed as an activity of conservation and business production.

A comprehensive review of natural compounds and their structure-activity relationship in Parkinson's disease: exploring potential mechanisms.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopamine-producing cells in the Substantia nigra region of the brain. Complementary and alternative medicine approaches have been utilized as adjuncts to conventional therapies for managing the symptoms and progression of PD. Naturalcompounds have gained attention for their potential neuroprotective effects and ability to target various pathways involved in the pathogenesis of PD. This comprehensive review aims to provide an in-depth analysis of the molecular targets and mechanisms of natural compounds in various experimental models of PD. This review will also explore the structure-activity relationship (SAR) of these compounds and assess the clinical studies investigating the impact of these natural compounds on individuals with PD. The insights shared in this review have the potential to pave the way for the development of innovative therapeutic strategies and interventions for PD.

Pterosin B improves cognitive dysfunction by promoting microglia M1/M2 polarization through inhibiting Klf5/Parp14 pathway

BackgroundPterosin B (PB) exhibits strong neuroprotective effects in vitro, but its therapeutic effect and underlying mechanism on Alzheimer's disease (AD) remain elusive. PurposeThis study aimed to investigate the anti-AD effect and mechanism of PB. Study designThe therapeutic effect and mechanism of PB were investigated in APP/PS1 mice and lipopolysaccharide (LPS)-induced BV-2 cells. MethodsAfter 8 weeks of oral administration of PB or donepezil, the cognitive function was assessed using behavioral tests. Pathological damage was evaluated using histological analysis and immunohistochemical staining. Flow cytometry was applied to detect M1/M2 polarization. The expression levels of glycolysis- and oxidative phosphorylation-related proteins as well as enzyme activities were determined using Western blot and biochemical kits, respectively. The levels of inflammatory cytokines and Kruppel-like factor 5 (Klf5) were measured using enzyme-linked immunosorbent assay. AD biomarkers in serum were analyzed using single-molecular array. RNA sequencing identified the downstream molecules of Klf5, and interaction was evaluated using dual-luciferase reporter assay. ResultsOur findings demonstrated that PB effectively ameliorated cognitive impairment and reduced pathological damage in APP/PS1 mice. Furthermore, PB facilitated the transition of the phenotype of LPS-induced BV-2 cells from M1 to M2 by modulating metabolic reprogramming. Additionally, Klf5 had high expression levels in the serum of patients with AD, which strongly correlated with cognitive performance and AD biomarkers. PB downregulated Klf5 expression both in vitro and in vivo. Subsequently, poly-ADP ribosyl polymerase 14 (Parp14) was identified as a downstream molecule of Klf5 involved in regulating metabolic reprogramming, and PB regulated microglia M1/M2 polarization by inhibiting the Klf5/Parp14 pathway. ConclusionThe findings suggested that PB ameliorated cognitive dysfunction in AD by modulating microglia M1/M2 polarization via inhibiting Klf5/Parp14 pathway.

Selective neuronal expression of progranulin is sufficient to provide neuroprotective and anti-inflammatory effects after traumatic brain injury

Progranulin (PGRN), which is produced in neurons and microglia, is a neurotrophic and anti-inflammatory glycoprotein. Human loss-of-function mutations cause frontotemporal dementia, and PGRN knockout (KO) mice are a model for dementia. In addition, PGRN KO mice exhibit severe phenotypes in models of traumatic or ischemic central nervous system (CNS) disorders, including traumatic brain injury (TBI). It is unknown whether restoration of progranulin expression in neurons (and not in microglia) might be sufficient to prevent excessive TBI-evoked brain damage. To address this question, we generated mice with Nestin-Cre-driven murine PGRN expression in a PGRN KO line (PGRN-KONestinGrn) to rescue PGRN in neurons. PGRN expression analysis in primary CNS cell cultures from naïve mice and in (non-) injured brain tissue from PGRN-KONestinGrn revealed expression of PGRN in neurons but not in microglia. After experimental TBI, examination of the structural brain damage at 5 days post-injury (dpi) showed that the TBI-induced loss of brain tissue and hippocampal neurons was exacerbated in PGRN-KOGrnflfl mice (PGRN knockout with the mGrn fl-STOP-fl allele, Cre-negative), as expected, whereas the tissue damage in PGRN-KONestinGrn mice was similar to that in PGRN-WT mice. Analysis of CD68+ immunofluorescent microglia and Cd68 mRNA expression showed that excessive microglial activation was rescued in PGRN-KONestinGrn mice, and the correlation of brain injury with Cd68 expression suggested that Cd68 was a surrogate marker for excessive brain injury caused by PGRN deficiency. The results show that restoring neuronal PGRN expression was sufficient to rescue the exacerbated neuropathology of TBI caused by PGRN deficiency, even in the absence of microglial PGRN. Hence, endogenous microglial PGRN expression was not essential for the neuroprotective or anti-inflammatory effects of PGRN after TBI in this study.Graphical

Edaravone Dexborneol provides neuroprotective effect by inhibiting neurotoxic activation of astrocytes through inhibiting NF-κB signaling in cortical ischemia

Edaravone Dexborneol (EDB), comprised of edaravone and (+)- bornel, has been demonstrated to have synergistic effects of antioxidant and anti-inflammatory, which makes it to be applied for stroke as a protectant. However, the underlying mechanism of neuroprotection of EDB has not been fully elucidated. Increasing evidence has shown that neurotoxic A1 astrocytes were closely related to neuronal death after cerebral ischemia. However, whether EDB could provide neuroprotection by modulating the activation of astrocytes has not yet been elucidated. The present study aimed to explore whether EDB afforded neuroprotection by modulating A1 polarization of astrocytes and the down-stream signaling after cerebral ischemia. We first validated the neuroprotective effects of EDB in mice suffering focal cerebral ischemia via evaluating behavioral test, infarct volumes and neuronal survival. As for the down-stream signaling, our data further showed that EDB alleviated neuronal death by suppressing activation of neurotoxic A1 astrocytes via inhibition of NF-κB signaling pathway in vitro. Additionally, administration of EDB reduced the number of A1 reactive astrocytes in mice of focal cerebral ischemia. The above findings demonstrated that EDB provided neuroprotective effect by inhibiting neurotoxic activation of A1 astrocytes in animal model of cerebral ischemia, which indicated that EDB-mediated phenotypic regulation of astrocytes is a potential research direction to promote neurological recovery in central nervous system (CNS) diseases.

Regulatory Peptide Pro-Gly-Pro Accelerates Neuroregeneration of Primary Neuroglial Culture after Mechanical Injury in Scratch Test

The scratch test is used as an experimental in vitro model of mechanical damage to primary neuronal cultures to study the mechanisms of cell death in damaged areas. The involvement of NMDA receptors in processes leading to delayed neuronal death, due to calcium dysregulation and synchronous mitochondrial depolarization, has been previously demonstrated. In this study, we explored the neuroregenerative potential of Pro-Gly-Pro (PGP)—an endogenous regulatory peptide with neuroprotective and anti-inflammatory properties and a mild chemoattractant effect. Mechanical injury to the primary neuroglial culture in the form of a scratch caused acute disruption of calcium homeostasis and mitochondrial functions. This was accompanied by neuronal death alongside changes in the profile of neuronal markers (BDNF, NSE and GFAP). In another series of experiments, under subtoxic doses of glutamate (Glu, 33 μM), delayed changes in [Ca2+]i and ΔΨm, i.e., several days after scratch application, were more pronounced in cells in damaged neuroglial cultures. The percentage of cells that restored the initial level of [Ca2+]i (p < 0.05) and the rate of recovery of ΔΨm (p < 0.01) were decreased compared with undamaged cells. Prophylactic application of PGP (100 μM, once) prevented the increase in [Ca2+]i and the sharp drop in mitochondrial potential [ΔΨm] at the time of scratching. Treatment with PGP (30 μM, three or six days) reduced the delayed Glu-induced disturbances in calcium homeostasis and cell death. In the post-glutamate period, the surviving neurons more effectively restored the initial levels of [Ca2+]i (p < 0.001) and Ψm (p < 0.0001). PGP also increased intracellular levels of BDNF and reduced extracellular NSE. In the context of the peptide’s therapeutic effect, the recovery of the damaged neuronal network occurred faster due to reduced astrogliosis and increased migration of neurons to the scratch area. Thus, the peptide PGP has a neuroprotective effect, increasing the survival of neuroglial cells after mechanical trauma in vitro by reducing cellular calcium overload and preventing mitochondrial dysfunction. Additionally, the tripeptide limits the post-traumatic consequences of mechanical damage: it reduces astrogliosis and promotes neuronal regeneration.

Clausena harmandiana root extract ameliorates Aβ1-42 induced cognitive deficits, oxidative stress, and apoptosis in rats

BackgroundClausena harmandiana (CH), commonly known as song fa dong, was a medicinal plant traditionally used to treat illnesses and as a health tonic. CH root extract (CHRE) exhibited various bioactivities, including neuroprotective, antioxidant, antimicrobial, antifungal, anti-inflammatory, and anti-cancer effects. However, CHRE data on neuroprotective in AD-like animal models were still scarce.ObjectivesThis study aimed to investigate the effects of CHRE on Aβ1-42-induced cognitive deficits, free radical damage, and neuronal death in rats.MethodsForty-eight adult male Sprague-Dawley rats (250–300 g) were classified as sham control (SC), V+Aβ, Vit C+Aβ, CHRE125+Aβ, CHRE250+Aβ, and CHRE500+Aβ (n = 8 in each group). Animals were orally administered with 0.5% sodium carboxymethylcellulose, vitamin C (200 mg/kg BW), or CHRE (125, 250, and 500 mg/kg BW) and were untreated for 35 days. On day 21, all treated rats were injected with 1 µl of aggregated Aβ1-42 (1 µg/µl) into the lateral ventricles, bilaterally, whereas untreated rats were injected with sterilized normal saline (NS). The Morris water maze test estimated the rat’s learning and memory one week later. At the end of the treatment, all rats were sacrificed, and their brains were removed and divided into two hemispheres. On the left, morphological changes and neuronal density were observed in hippocampal CA1 and CA3 regions. While, on the right, changes in free radical damage markers (SOD, CAT, GPx, MDA, and Nrf2) and protein expression of active caspase-3 were evaluated in the hippocampus.ResultsPretreatment with CHRE at all doses could alleviate spatial learning and memory defects. CHRE also improved morphological changes and a decrease in neuronal density in CA1 and CA3 regions. Additionally, CHRE significantly increased the activities of antioxidant enzymes (SOD, CAT, GPx) and Nrf2 expression. This was coupled with significantly decreased MDA levels and active caspase-3 expression in the hippocampus of Aβ1-42-induced rats, which was similar to vitamin C exposure.ConclusionsOur findings suggested that CHRE ameliorated cognitive deficits and exhibited neuroprotective effects by reducing free radical damage and mitigating neuronal abnormality and neuronal death.

Identification of 3-methyl-1-(3-methylpyridin-2-yl)-1H-pyrazol-5-ol as promising neuroprotective agent

Pyrazolol derivatives are gaining significant attention for their diverse pharmacological effects, such as analgesic, anti-inflammatory, antioxidant, and anticancer activities. In this study, 20 pyrazolol derivatives were designed and synthesized to develop an anti-ischemic stroke formulation with free radical scavenging activity. Most of these synthesized compounds demonstrated antioxidant capabilities in DPPH, ABTS radical scavenging, and ORACFL assays. The methyl-substituted compound Y12, in particular, showed exceptional antioxidant capacity. Additionally, these compounds showed excellent neurocytoprotective effects in the SH-SY5Y cell injury model subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Notably, Y12 exhibited significant metal chelating activity with Cu2+. In vivo studies confirmed that compound Y12 has neuroprotective effects and can significantly reduce the infarct area in a mouse model of focal cerebral ischemia induced by transient middle cerebral artery occlusion (tMCAO).

Role of Medicinal Plants in the Management of Multiple Sclerosis.

There is a rapid spread of Multiple Sclerosis disorder across the globe, around 2.8 million cases of Multiple Sclerosis in the world. Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by demyelination, neuroinflammation, and a wide spectrum of clinical manifestations. Many drugs have been tested on MS patients but there is no effective treatment for MS till now. So to inhibit the symptoms caused by MS we performed a study in which we identified various naturally occurring materials with neuroprotective effects on the body that can treat Multiple Sclerosis. The therapeutic strategies portion of the paper reviews the array of disease-modifying therapies currently available for MS management. This paper evaluated their mechanisms of action, efficacy, and safety profiles. It also addressed emerging treatment paradigms by using different naturally occurring materials, including personalized medicine approaches and novel therapies in development. This paper provides a comprehensive overview of the current state of knowledge regarding MS, focusing on its pathogenesis, diagnostic approaches, and therapeutic strategies.

TBC1D15-regulated mitochondria–lysosome membrane contact exerts neuroprotective effects by alleviating mitochondrial calcium overload in seizure

Mitochondrial calcium overload plays an important role in the neurological insults in seizure. The Rab7 GTPase-activating protein, Tre-2/Bub2/Cdc16 domain family member 15 (TBC1D15), is involved in the regulation of mitochondrial calcium dynamics by mediating mitochondria–lysosome membrane contact. However, whether TBC1D15-regulated mitochondria–lysosome membrane contact and mitochondrial calcium participate in neuronal injury in seizure is unclear. We aimed to investigate the effect of TBC1D15-regulated mitochondria–lysosome membrane contact on epileptiform discharge-induced neuronal damage and further explore the underlying mechanism. Lentiviral vectors (Lv) infection and stereotaxic adeno-associated virus (AAV) injection were used to regulate TBC1D15 expression before establishing in vitro epileptiform discharge and in vivo status epilepticus (SE) models. TBC1D15’s effect on inter-organellar interactions, mitochondrial calcium levels and neuronal injury in seizure was evaluated. The results showed that abnormalities in mitochondria–lysosome membrane contact, mitochondrial calcium overload, mitochondrial dysfunction, increased levels of reactive oxygen species, and prominent neuronal damage were partly relieved by TBC1D15 overexpression, whereas TBC1D15 knockdown markedly deteriorated these phenomena. Further examination revealed that epileptiform discharge-induced mitochondrial calcium overload in primary hippocampal neurons was closely associated with abnormal mitochondria–lysosome membrane contact. This study highlights the crucial role played by TBC1D15-regulated mitochondria–lysosome membrane contact in epileptiform discharge-induced neuronal injury by alleviating mitochondrial calcium overload.

Early transtympanic administration of rhBDNF exerts a multifaceted neuroprotective effect against cisplatin-induced hearing loss.

Cisplatin-induced sensorineural hearing loss is a significant clinical challenge. Although the potential effects of brain-derived neurotrophic factor (BDNF) have previously been investigated in some ototoxicity models, its efficacy in cisplatin-induced hearing loss remains uncertain. This study aimed to investigate the therapeutic potential of recombinant human BDNF (rhBDNF) in protecting cells against cisplatin-induced ototoxicity. Using an in vivo model of cisplatin-induced hearing loss, we investigated the beneficial effects of transtympanic administration of rhBDNF in a thermogel solution on hearing function and cochlear injury, using electrophysiological, morphological, immunofluorescence and molecular analyses. Our data showed that local rhBDNF treatment counteracted hearing loss in rats receiving cisplatin by preserving synaptic connections in the cochlear epithelium and protecting hair cells (HCs) and spiral ganglion neurons (SGNs) against cisplatin-induced cell death. Specifically, rhBDNF maintains the balance of its receptor levels (pTrkB and p75), boosting TrkB-CREB pro-survival signalling and reducing caspase 3-dependent apoptosis in the cochlea. Additionally, it activates antioxidant mechanisms while inhibiting inflammation and promoting vascular repair. Collectively, we demonstrated that early transtympanic treatment with rhBDNF plays a multifaceted protective role against cisplatin-induced ototoxicity, thus holding promise as a novel potential approach to preserve hearing in adult and paediatric patients undergoing cisplatin-based chemotherapy.

Hormone Replacement Therapy and Alzheimer's Disease: Current State of Knowledge and Implications for Clinical Use.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder responsible for over half of dementia cases, with two-thirds being women. Growing evidence from preclinical and clinical studies underscores the significance of sex-specific biological mechanisms in shaping AD risk. While older age is the greatest risk factor for AD, other distinct biological mechanisms increase the risk and progression of AD in women including sex hormones, brain structural differences, genetic background, immunomodulation and vascular disorders. Research indicates a correlation between declining estrogen levels during menopause and an increased risk of developing AD, highlighting a possible link with AD pathogenesis. The neuroprotective effects of estrogen vary with the age of treatment initiation, menopause stage, and type. This review assesses clinical and observational studies conducted in women, examining the influence of estrogen on cognitive function or addressing the ongoing question regarding the potential use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. This review covers recent literature and discusses the working hypothesis, current use, controversies and challenges regarding HRT in preventing and treating age-related cognitive decline and AD. The available evidence indicates that estrogen plays a significant role in influencing dementia risk, with studies demonstrating both beneficial and detrimental effects of HRT. Recommendations regarding HRT usage should carefully consider the age when the hormonal supplementation is initiated, baseline characteristics such as genotype and cardiovascular health, and treatment duration until this approach can be more thoroughly investigated or progress in the development of alternative treatments can be made.

ERO1A inhibition mitigates neuronal ER stress and ameliorates UBQLN2ALS phenotypes in Drosophila melanogaster

Modulating the ER stress pathway holds therapeutic promise for neurodegenerative diseases; however, identifying optimal targets remains challenging. In this study, we conducted an unbiased screening to systematically search for commonly up-regulated proteins in ER stress-related neurodegenerative conditions, with endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) emerging as a significant hit. Further experiments conducted in the model organism Drosophila melanogaster demonstrated that elevated levels of Drosophila ERO1A (ERO1L) were indeed detrimental to neurons. Conversely, genetic suppression or pharmacological inhibition of ERO1L activity provided neuroprotection under ER stress and extended the lifespan of flies. To translate these findings, we performed a genetic modifier screening and underscored significant neuroprotective effects against UBQLN2ALS pathology. Additionally, administration of the chemical probe inhibitor of ERO1A, known as EN460, enhanced locomotive functions and neuromuscular junction (NMJ) morphology in Drosophila UBQLN2ALS model. Mechanistically, targeting ERO1L during environmental or pathological ER stress mitigated proteotoxic stress by lowering either the PERK or IRE1 branches of the unfolded protein response (UPR). These findings suggest ERO1A as a promising therapeutic target in UBQLN2ALS and other ER stress-related conditions.

The therapeutic potential of reduced graphene oxide in attenuating cuprizone-induced demyelination in mice.

Reduced Graphene Oxide (rGO) has unique physicochemical properties that make it suitable for therapeutic applications in neurodegenerative scenarios. This study investigates the therapeutic potential of rGO in a cuprizone-induced demyelination model in mice through histomorphological techniques and analysis of biochemical parameters. We demonstrate that daily intraperitoneal administration of rGO (1 mg/ml) for 21 days tends to reduce demyelination in the Corpus callosum by decreasing glial cell recruitment during the repair mechanism. Additionally, rGO interferes with oxidative stress markers in the brain and liver indicating potential neuroprotective effects in the central nervous system (CNS). No significant damage to vital organs was observed, suggesting that multiple doses could be used safely. However, further long-term investigations are needed to understand rGO distribution, metabolism, routes of action and associated challenges in central neurodegenerative therapies. Overall, these findings contribute to the comprehension of rGO effects in vivo, paving the way for possible future clinical research.

Microglia-mediated endothelial protection: the role of SHPL-49 in ischemic stroke

It was previously shown that SHPL-49, a glycoside derivative of salidroside formed through structural modification, exhibited neuroprotective effects in a rat cerebral ischemia model of permanent middle cerebral artery occlusion (pMCAO). Additionally, SHPL-49 enhanced the mRNA expression of vascular endothelial growth factor-a (Vegf-a) in macrophages. Microglia, functioning as resident macrophages within the brain, promptly respond to cerebral ischemia and engage in interactions with the cells of the Glial-Vascular Unit to orchestrate nerve injury responses. We postulated that the neuroprotective effects of SHPL-49 were mediated through microglia-dependent amelioration of endothelial dysfunction following cerebral ischemia. The present study demonstrates that SHPL-49 effectively mitigated microglia-dependent endothelial dysfunction in the pMCAO model by upregulating the expression of VEGF and suppressing the release of MMP-9 from microglia. Further MRI analyses confirmed that SHPL-49 significantly reduced nerve and endothelial function when microglia were depleted in the brains of pMCAO rats. The above phenomenon was also confirmed in the in vitro experiment investigating microglia-mediated brain endothelial cell function. Furthermore, we discovered that SHPL-49 activates the VEGFR2/Akt/eNOS pathways in endothelial cells and suppresses the p38 MAPK/MMP-9 pathways in microglia cells, thereby facilitating brain endothelial cell protection. Altogether, we have demonstrated that SHPL-49 effectively ameliorates endothelial dysfunction induced by cerebral ischemia through a microglia-dependent mechanism, thereby providing more valuable insights and references for the clinical evaluation of SHPL-49 injection for ischemic stroke.

Formulation and optimization of fisetin nanoemulsion for the treatment of Alzheimer's disease in rats: Pharmacokinetic and pharmacodynamic assessment

Fiestin (FS) is a polyphenolic flavonoid that possesses various neuroprotective effects by attenuating the levels of AChE enzyme, accumulated amyloid β, free radicals and neuroinflammation against Alzheimer's disease (AD). It is also helpful in reducing cellular senescence. However, FS suffers from a dissolution rate-limited oral bioavailability, and poor blood-brain barrier (BBB) permeability leading to decreased therapeutic efficacy. To address these challenges, an attempt has been made to formulate a nanoemulsion (NE) of FS using Box-Behnken design (BBD) as optimization tool. The optimized NE contained 10 mg of FS, 164 μL of Capmul MCM EP/NF® (oil), 618 μL of T80 (surfactant), 218 μL of Transcutol P®, (co-surfactant) and 4000 μL of distilled water. The optimized formulation resulted in a mean droplet size, drug loading, polydispersity index (PDI), and zeta potential (ZP) of 32 nm, 95.5 %, 0.26, and −15.99 mV, respectively. In the pharmacokinetic studies, FS-NE showed 9.2-fold increase in Cmax as compared to naïve FS. Relative oral bioavailability FS loaded in FS-NE was 842.93 %. Further the concentration of FS loaded in FS-NE was 8.81-fold higher in brain than naive FS. To evaluate pharmacodynamic effects, an aluminum chloride (AlCl3)-induced AD rat model was used. Cognitive functions were assessed using the Morris water maze and open field tests. The formulation showed dose-dependent effects. Rats treated with both, low and high doses of FS-NE (groups VI and VII) showed significant improvements (P < 0.001) in cognitive functions in AD-induced rats. The biochemical studies showed that FS-NE at both doses attenuated the levels of AChE enzyme, amyloid β, oxidative stress, and neuroinflammation. Results of histopathology indicated that FS-NE attenuated the degeneration of neurons in the cerebral cortex and hippocampus parts of the brain.

Decoding the Therapeutic Potential of Cannabis and Cannabinoids in Neurological Disorders.

For millennia, Cannabis sativa has served diverse roles, from medicinal applications to recreational use. Despite its extensive historical use, only a fraction of its components have been explored until recent times. The therapeutic potential of Cannabis and its constituents has garnered attention, with suggestions for treating various conditions such as Parkinson's disease, epilepsy, Alzheimer's disease, and other Neurological disorders. Recent research, particularly on animal experimental models, has unveiled the neuroprotective properties of cannabis. This neuroprotective effect is orchestrated through numerous G protein-coupled receptors (GPCRs) and the two cannabinoid receptors, CB1 and CB2. While the capacity of cannabinoids to safeguard neurons is evident, a significant challenge lies in determining the optimal cannabinoid receptor agonist and its application in clinical trials. The intricate interplay of cannabinoids with the endocannabinoid system, involving CB1 and CB2 receptors, underscores the need for precise understanding and targeted approaches. Unravelling the molecular intricacies of this interaction is vital to harness the therapeutic potential of cannabinoids effectively. As the exploration of cannabis components accelerates, there is a growing awareness of the need for nuanced strategies in utilizing cannabinoid receptor agonists in clinical settings. The evolving landscape of cannabis research presents exciting possibilities for developing targeted interventions that capitalize on the neuroprotective benefits of cannabinoids while navigating the complexities of receptor specificity and clinical applicability.