The role of chitosan in mitigating tert-butylhydroquinone induced cognitive impairment and neurotoxicity in a rat model.

OBJECTIVE: This study aimed to investigate the impact of tert-butylhydroquinone (TBHQ), chitosan, and their combination on memory and neurobiochemical parameters in a rat model. The primary objectives were to assess the cognitive effects of TBHQ, explore the cognitive-enhancing properties of chitosan, and evaluate the combined effects of these substances. MATERIALS AND METHODS: A rat model was employed for behavioral tests, biochemical analyses, and histological examinations. Rats were exposed to TBHQ, chitosan, or a combination of both, and cognitive function was assessed through behavioral tests. Biochemical analyses focused on neurobiochemical parameters associated with memory and oxidative stress. Histological examinations were conducted to observe any structural changes in the brain. RESULTS: TBHQ exposure was associated with memory impairments and increased oxidative stress, indicating potential neurotoxic effects. Chitosan supplementation demonstrated cognitive-enhancing effects and showed promise in mitigating the memory impairments and oxidative stress induced by TBHQ. The combination of chitosan and TBHQ presented a potential protective effect on neurological health. CONCLUSIONS: Chitosan supplementation alongside TBHQ may mitigate memory impairments and oxidative stress associated with TBHQ exposure in a rat model. The study provides valuable insights into the cognitive effects of TBHQ and the neuroprotective potential of chitosan, highlighting the need for further research to elucidate molecular pathways and clinical implications. These findings contribute to understanding chitosan's role in safeguarding neurological health in conditions where TBHQ exposure is a concern, warranting further investigations for translational applications in human health.

Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection.

Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Studies have demonstrated that the retina in patients with Parkinson's disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells-a sensitive neuron in the retina-at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson's disease and retinal ganglion cell injury.

Treatment with inhaled Argon: a systematic review of pre-clinical and clinical studies with meta-analysis on neuroprotective effect.

BACKGROUND: Argon (Ar) has been proposed as a potential therapeutic agent in multiple clinical conditions, specifically in organ protection. However, conflicting data on pre-clinical models, together with a great variability in Ar administration protocols and outcome assessments, have been reported. The aim of this study was to review evidence on treatment with Ar, with an extensive investigation on its neuroprotective effect, and to summarise all tested administration protocols. METHODS: Using the PubMed database, all existing pre-clinical and clinical studies on the treatment with Ar were systematically reviewed (registration: https://doi.org/10.17605/OSF.IO/7983D). Study titles and abstracts were screened, extracting data from relevant studies post full-text review. Exclusion criteria included absence of full text and non-English language. Furthermore, meta-analysis was also performed to assess Ar potential as neuroprotectant agent in different clinical conditions: cardiac arrest, traumatic brain injury, ischemic stroke, perinatal hypoxic-ischemic encephalopathy, subarachnoid haemorrhage. Standardised mean differences for neurological, cognitive and locomotor, histological, and physiological measures were evaluated, through appropriate tests, clinical, and laboratory variables. In vivo studies were evaluated for risk of bias using the Systematic Review Center for Laboratory Animal Experimentation tool, while in vitro studies underwent assessment with a tool developed by the Office of Health Assessment and Translation. FINDINGS: The systematic review detected 60 experimental studies (16 in vitro, 7 ex vivo, 31 in vivo, 6 with both in vitro and in vivo) investigating the role of Ar. Only one clinical study was found. Data from six in vitro and nineteen in vivo studies were included in the meta-analyses. In pre-clinical models, Ar administration resulted in improved neurological, cognitive and locomotor, and histological outcomes without any change in physiological parameters (i.e., absence of adverse events). INTERPRETATION: This systematic review and meta-analysis based on experimental studies supports the neuroprotective effect of Ar, thus providing a rationale for potential translation of Ar treatment in humans. Despite adherence to established guidelines and methodologies, limitations in data availability prevented further analyses to investigate potential sources of heterogeneity due to study design. FUNDING: This study was funded in part by Italian Ministry of Health-Current researchIRCCS and by Ministero della Salute Italiano, Ricerca Finalizzata, project no. RF 2019-12371416.

Efficacy of Citicoline Delivered via Brain Extracellular Space against Experimental Acute Ischemic Stroke in Rats.

Objective: Citicoline can be used to reduce acute ischemic stroke injury via venous infusion, however, its protective effects in the brain extracellular space remain largely unknown. Herein, we investigated the brain protective effects of citicoline administered via the brain extracellular space and sought precise effective dosage range that can protect against ischemic injury after experimental ischemic stroke in rats. Methods: Fifty-six Sprague-Dawley rats were randomly divided into control, intraperitoneal (IP), caudate-putamen (CPu)-25, CPu-40, CPu-50, CPu-60 and CPu-75 groups based on the infusion site and concentration of citicoline. Two hours after the administration of citicoline, the rats were subjected to a permanent middle cerebral artery occlusion to mimic acute ischemic stroke. Then, the brain infarct volume in rats after stroke was measured and their neurological deficiency was evaluated to explain the protective effects and effective dosage range of citicoline. Results: Compared to the control and IP groups, brain infarct volume of rats in CPu-40, CPu-50, and CPu-60 groups is significant smaller. Furthermore, the brain infarct volume of rats in CPu-50 is the least. Conclusions: Here, we showed that citicoline can decrease the brain infarct volume, thus protecting the brain from acute ischemic stroke injury. We also found that the appropriate effective citicoline dose delivered via the brain extracellular space is 50 mM. Our study provides novel insights into the precise treatment of acute ischemic stroke by citicoline via the brain extracellular space, further guiding the treatment of brain disease.

Omega-3 fatty acid diglyceride emulsions as a novel injectable acute therapeutic in neonatal hypoxic-ischemic brain injury.

Hypoxic-ischemic encephalopathy (HIE), resulting from a lack of blood flow and oxygen before or during newborn delivery, is a leading cause of cerebral palsy and neurological disability in children. Therapeutic hypothermia (TH), the current standard of care in HIE, is only beneficial in 1 of 7-8 cases. Therefore, there is a critical need for more efficient treatments. We have previously reported that omega-3 (n-3) fatty acids (FA) carried by triglyceride (TG) lipid emulsions provide neuroprotection after experimental hypoxic-ischemic (HI) injury in neonatal mice. Herein, we propose a novel acute therapeutic approach using an n-3 diglyceride (DG) lipid emulsions. Importantly, n-3 DG preparations had much smaller particle size compared to commercially available or lab-made n-3 TG emulsions. We showed that n-3 DG molecules have the advantage of incorporating at substantially higher levels than n-3 TG into an in vitro model of phospholipid membranes. We also observed that n-3 DG after parenteral administration in neonatal mice reaches the bloodstream more rapidly than n-3 TG. Using neonatal HI brain injury models in mice and rats, we found that n-3 DG emulsions provide superior neuroprotection than n-3 TG emulsions or TH in decreasing brain infarct size. Additionally, we found that n-3 DGs attenuate microgliosis and astrogliosis. Thus, n-3 DG emulsions are a superior, promising, and novel therapy for treating HIE.

Crocin ameliorates neuroinflammation and cognitive impairment in mice with Alzheimer's disease by activating PI3K/AKT pathway.

BACKGROUND: Crocin has a good prospect in the treatment of Alzheimer's disease (AD), but the mechanisms underlying its neuroprotective effects remain elusive. This study aimed to investigate the neuroprotective effects of Crocin and its underlying mechanisms in AD. METHODS: AD mice were set up by injecting Aß25-35 solution into the hippocampus. Then, the AD mice were injected intraperitoneally with 40 mg/kg/day of Crocin for 14 days. Following the completion of Crocin treatment, an open-field test, Y-maze test and Morris water maze test were conducted to evaluate the impact of Crocin on spatial learning and memory deficiency in mice. The effects of Crocin on hippocampal neuron injury, proinflammatory cytokine expressions (IL-1ß, IL-6, and TNF-α), and PI3K/AKT signaling-related protein expressions were measured using hematoxylin and eosin staining, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) experiments, respectively. RESULTS: Crocin attenuated Aß25-35-induced spatial learning and memory deficiency and hippocampal neuron injury. Furthermore, the Western blot and qRT-PCR results showed that Crocin effectively suppressed inflammation and activated the PI3K/AKT pathway in Aß25-35-induced mice. CONCLUSION: Crocin restrained neuroinflammation via the activation of the PI3K/AKT pathway, thereby ameliorating the cognitive dysfunction of AD mice.

Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone. MECHANISM OF ACTION: The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals. PHARMACOKINETICS: Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates. CLINICAL TRIALS: The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure. THERAPEUTIC ADVANCE: Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.

Arbutin intervention ameliorates memory impairment in a rat model of lysolecethin induced demyelination: Neuroprotective and anti-inflammatory effects.

Cognitive impairment (CI) and memory deficit are prevalent manifestations of multiple sclerosis (MS). This study explores the therapeutic potential of arbutin on memory deficits using a rat hippocampal demyelination model induced by lysophosphatidylcholine (LPC). Demyelination was induced by bilateral injection of 1% LPC into the CA1 area of the hippocampus, and the treated group received daily arbutin injections (50 mg/kg, i.p) for two weeks. Arbutin significantly improved memory impairment 14 days post-demyelination as assessed by Morris water maze test. Histological and immunohistochemical analyses demonstrated that arbutin reduced demyelination suppressed pro-inflammatory markers (IL-1ß, TNF-α) and increased anti-inflammatory cytokine IL-10. Arbutin also diminished astrocyte activation, decreased iNOS, enhanced anti-oxidative factors (Nrf2, HO-1), and exhibited neuroprotective effects by elevating myelin markers (MBP) and brain derived neurotrophic factor (BDNF). These findings propose arbutin as a potential therapeutic candidate for multiple sclerosis-associated memory deficits, warranting further clinical exploration.

The impact of Nrf2 knockout on the neuroprotective effects of dexmedetomidine in a mice model of cognitive impairment.

The nuclear factor erythroid 2-related factor 2 (Nrf2) signalling pathway represents a crucial intrinsic protective system against oxidative stress and inflammation and plays a significant role in various neurological disorders. However, the effect of Nrf2 signalling on the regulation of cognitive impairment remains unknown. Dexmedetomidine (DEX) has neuroprotective effects and can ameliorate lipopolysaccharide (LPS)-induced cognitive dysfunction. Our objective was to observe whether Nrf2 knockout influences the efficacy of DEX in improving cognitive impairment and to attempt to understand its underlying mechanisms. An LPS-induced cognitive dysfunction model in wild-type and Nrf2 knockout mice (Institute of Cancer Research background; male; 8-12 weeks) was used to observe the impact of DEX on cognitive dysfunction. LPS was intraperitoneally injected, followed by novel object recognition and morris water maze experiments 24 h later. Hippocampal tissues were collected for histopathological and molecular analyses. Our research findings suggest that DEX enhances the expression of NQO1, HO-1, PSD95, and SYP proteins in hippocampal tissue, inhibits microglial proliferation, reduces pro-inflammatory cytokines IL-1ß and TNF-ɑ, increases anti-inflammatory cytokine IL-10, and improves dendritic spine density, thereby alleviating cognitive dysfunction induced by LPS. However, the knockout of the Nrf2 gene negated the aforementioned effects of DEX. In conclusion, DEX alleviates cognitive deficits induced by LPS through mechanisms of anti-oxidative stress and anti-inflammation, as well as by increasing synaptic protein expression and dendritic spine density. However, the knockout of the Nrf2 gene reversed the effects of DEX. The Nrf2 signaling pathway plays a crucial role in the mitigation of LPS-induced cognitive impairment by DEX.

Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Effects of Mild Closed-Head Injury and Subanesthetic Ketamine Infusion on Microglia, Axonal Injury, and Synaptic Density in Sprague-Dawley Rats.

Mild traumatic brain injury (mTBI) affects millions of people in the U.S. Approximately 20-30% of those individuals develop adverse symptoms lasting at least 3 months. In a rat mTBI study, the closed-head impact model of engineered rotational acceleration (CHIMERA) produced significant axonal injury in the optic tract (OT), indicating white-matter damage. Because retinal ganglion cells project to the lateral geniculate nucleus (LGN) in the thalamus through the OT, we hypothesized that synaptic density may be reduced in the LGN of rats following CHIMERA injury. A modified SEQUIN (synaptic evaluation and quantification by imaging nanostructure) method, combined with immunofluorescent double-labeling of pre-synaptic (synapsin) and post-synaptic (PSD-95) markers, was used to quantify synaptic density in the LGN. Microglial activation at the CHIMERA injury site was determined using Iba-1 immunohistochemistry. Additionally, the effects of ketamine, a potential neuroprotective drug, were evaluated in CHIMERA-induced mTBI. A single-session repetitive (ssr-) CHIMERA (3 impacts, 1.5 joule/impact) produced mild effects on microglial activation at the injury site, which was significantly enhanced by post-injury intravenous ketamine (10 mg/kg) infusion. However, ssr-CHIMERA did not alter synaptic density in the LGN, although ketamine produced a trend of reduction in synaptic density at post-injury day 4. Further research is necessary to characterize the effects of ssr-CHIMERA and subanesthetic doses of intravenous ketamine on different brain regions and multiple time points post-injury. The current study demonstrates the utility of the ssr-CHIMERA as a rodent model of mTBI, which researchers can use to identify biological mechanisms of mTBI and to develop improved treatment strategies for individuals suffering from head trauma.

Extracellular vesicle encapsulated nicotinamide delivered via a trans-scleral route provides retinal ganglion cell neuroprotection.

The progressive and irreversible degeneration of retinal ganglion cells (RGCs) and their axons is the major characteristic of glaucoma, a leading cause of irreversible blindness worldwide. Nicotinamide adenine dinucleotide (NAD) is a cofactor and metabolite of redox reaction critical for neuronal survival. Supplementation with nicotinamide (NAM), a precursor of NAD, can confer neuroprotective effects against glaucomatous damage caused by an age-related decline of NAD or mitochondrial dysfunction, reflecting the high metabolic activity of RGCs. However, oral supplementation of drug is relatively less efficient in terms of transmissibility to RGCs compared to direct delivery methods such as intraocular injection or delivery using subconjunctival depots. Neither method is ideal, given the risks of infection and subconjunctival scarring without novel techniques. By contrast, extracellular vesicles (EVs) have advantages as a drug delivery system with low immunogeneity and tissue interactions. We have evaluated the EV delivery of NAM as an RGC protective agent using a quantitative assessment of dendritic integrity using DiOlistics, which is confirmed to be a more sensitive measure of neuronal health in our mouse glaucoma model than the evaluation of somatic loss via the immunostaining method. NAM or NAM-loaded EVs showed a significant neuroprotective effect in the mouse retinal explant model. Furthermore, NAM-loaded EVs can penetrate the sclera once deployed in the subconjunctival space. These results confirm the feasibility of using subconjunctival injection of EVs to deliver NAM to intraocular targets.

Exploring the potential of quercetin in Alzheimer's Disease: Pharmacodynamics, Pharmacokinetics, and Nanodelivery systems.

Alzheimer's disease (AD) is a primary cause of dementia that affects millions of people worldwide and its prevalence is likely to increase largely in the coming decades. Multiple complex pathways, such as oxidative stress, tau and amyloid-beta (Aß) pathology, and cholinergic dysfunction, are involved in the pathogenesis of Alzheimer's disease. The conventional treatments provide only symptomatic relief and not a complete cure for the disease. On the other hand, recent studies have looked into the possibility of flavonoids as an effective therapeutic strategy for treating AD. Quercetin, a well-known flavonol, has been extensively studied for AD treatment. Therefore, this review mainly focuses on the pharmacokinetics properties of quercetin and its modes of action, such as antioxidant, anti-inflammatory, anti-amyloidogenic, and neuroprotective properties, which are beneficial in treating AD. It also highlights the nano delivery systems of quercetin, including liposomes, nanostructures lipid carriers, solid lipid nanoparticles, nanoemulsions, microemulsions, self-emulsifying drug delivery systems, and nanoparticles reported for AD treatment. The remarkable potential of quercetin nanocarriers has been reflected in enhancing its bioavailability and therapeutic efficacy. Therefore, clinical studies must be conducted to explore it as a therapeutic strategy for Alzheimer's disease.

Timing of administration of antenatal magnesium sulphate and correlation with umbilical cord blood magnesium levels in preterm babies.

BACKGROUND: The effectiveness of MgSO4 for foetal neuroprotection is acknowledged, but the best time to provide it in relation to birth is a conundrum, and dose schedule is yet unknown. Understanding the determinants of the magnesium levels in cord blood aids in determining the appropriate timing and length of administration. AIM AND OBJECTIVE: To assess the cord blood magnesium concentration in relation to the timing of MgSO4 and delivery. To achieve ROC in relation to optimum level of cord blood magnesium concentration in relation to neonatal outcome variables. STUDY DESIGN: A prospective observational study conducted in a tertiary care hospital over 2 years in women having preterm delivery from 26 weeks to 33 + 6 weeks, who received Neuroprophylaxis. Cord blood was collected for magnesium level estimation. Baby followed 24 h after delivery. ROC analysis performed for predicting an optimal cut-off for a continuous predictor predicting binary outcome. RESULTS: 85 recruited cases divided into bolus group, bolus + infusion group. The mean cord blood magnesium (n = 85) was 3.8 mg/dl. The AUROC for Gestational Age at Administration predicting Baby Outcome: 0.699, It was statistically significant (p = 0.034). The AUROC for Cord Blood Mg predicting Baby Outcome: 0.606, It was not statistically significant (p = 0.262). CONCLUSION: Mean cord blood magnesium levels served as a tool to determine the timing and duration of Neuroprophylaxis. Mean cord blood magnesium of 3.8 mg/dl should be achieved to serve the purpose of Neuroprotection. To achieve this, Bolus followed by Infusion should be administered for at-least 6 h prior to delivery.

Remodeling brain pathological microenvironment to lessen cerebral ischemia injury by multifunctional injectable hydrogels.

Ischemia stroke is one of the leading causes of death and disability worldwide. Owing to the limited delivery efficiency to the brain caused by the blood-brain barrier (BBB) and off-target effects of systemic treatment, it is crucial to develop an in situ drug delivery system to improve the therapeutic effect in ischemic stroke. Briefly, we report a multifunctional in situ hydrogel delivery system for the co-delivery of reactive oxygen species (ROS)-responsive nanoparticles loaded with atorvastatin calcium (DSPE-se-se-PEG@AC NPs) and ß-nerve growth factor (NGF), which is expected to remodel pathological microenvironment for improving cerebral ischemia injury. The in vitro results exhibited the multifunctional hydrogel scavenged oxygen-glucose deprivation (OGD)-induced free radical, rescued the mitochondrial function, and maintained the survival and function of neurons, hence reducing neuronal apoptosis and neuroinflammation, consequently relieving ischemia injury in hippocampal neurons cell line (HT22). In the rat ischemia stroke model, the hydrogel significantly minified cerebral infarction by regulating inflammatory response, saving apoptotic neurons, and promoting angiogenesis and neurogenesis. Besides, the hydrogel distinctly improved the rats' neurological deficits after cerebral ischemia injury over the long-term observation. In conclusion, the in-situ hydrogel platform has demonstrated promising therapeutic effects in both in vitro and in vivo studies, indicating its potential as a new and effective therapy.

A sterilizable platform based on crosslinked xanthan gum for controlled-release of polymeric micelles: Ocular application for the delivery of neuroprotective compounds to the posterior eye segment.

TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) polymeric micelles show interesting properties for ocular administration thanks to their solubilization capability, nanometric size and tissue penetration ability. However, micelles formulations are generally characterized by low viscosity, poor adhesion and very short retention time at the administration site. Therefore, the idea behind this work is the preparation and characterization of a crosslinked film based on xanthan gum that contains TPGS micelles and is capable of controlling their release. The system was loaded with melatonin and cyclosporin A, neuroprotective compounds to be delivered to the posterior eye segment. Citric acid and heating at different times and temperatures were exploited as crosslinking approach, giving the possibility to tune swelling, micelles release and drug release. The biocompatibility of the platform was confirmed by HET-CAM assay. Ex vivo studies on isolated porcine ocular tissues, conducted using Franz cells and two-photon microscopy, demonstrated the potential of the xanthan gum-based platform and enlightened micelles penetration mechanism. Finally, the sterilization step was approached, and a process to simultaneously crosslink and sterilize the platform was developed.

Neuroprotective Effect of Sterculia setigera Leaves Hydroethanolic Extract.

Plants are a valuable source of information for pharmacological research and new drug discovery. The present study aimed to evaluate the neuroprotective potential of the leaves of the medicinal plant Sterculia setigera. In vitro, the effect of Sterculia setigera leaves dry hydroethanolic extract (SSE) was tested on cultured cerebellar granule neurons (CGN) survival when exposed to hydrogen peroxide (H2O2) or 6-hydroxydopamine (6-OHDA), using the viability probe fluorescein diacetate (FDA), a lactate dehydrogenase (LDH) activity assay, an immunocytochemical staining against Gap 43, and the quantification of the expression of genes involved in apoptosis, necrosis, or oxidative stress. In vivo, the effect of intraperitoneal (ip) injection of SSE was assessed on the developing brain of 8-day-old Wistar rats exposed to ethanol neurotoxicity by measuring caspase-3 activity on cerebellum homogenates, the expression of some genes in tissue extracts, the thickness of cerebellar cortical layers and motor coordination. In vitro, SSE protected CGN against H2O2 and 6-OHDA-induced cell death at a dose of 10 µg/mL, inhibited the expression of genes Casp3 and Bad, and upregulated the expression of Cat and Gpx7. In vivo, SSE significantly blocked the deleterious effect of ethanol by reducing the activity of caspase-3, inhibiting the expression of Bax and Tp53, preventing the reduction of the thickness of the internal granule cell layer of the cerebellar cortex, and restoring motor functions. Sterculia setigera exerts neuroactive functions as claimed by traditional medicine and should be a good candidate for the development of a neuroprotective treatment against neurodegenerative diseases.

Letter to editor: Serum concentration-guided intravenous magnesium sulfate administration for neuroprotection in patients with aneurysmal subarachnoid hemorrhage: A retrospective evaluation of a 12-year single-center experience.

This critique examines a 12-year retrospective study on serum magnesium concentration-guided administration of magnesium sulfate in 548 patients with aneurysmal subarachnoid hemorrhage (aSAH). The study reported that maintaining serum magnesium levels between 2 and 2.5 mmol/L reduced rates of delayed cerebral infarction and improved clinical outcomes. However, limitations due to its retrospective nature, single-center design, and unequal treatment group sizes may affect generalizability. Future multicentric randomized controlled trials are recommended to validate these findings and refine magnesium dosing strategies for aSAH treatment.

The neuroprotective effect of exogen melatonin upon fetal hippocampus damage caused by high-dose caffeine administration in pregnant rats.

OBJECTIVE: The aim of this study is to evaluate whether exogenous melatonin (MEL) mitigates the deleterious effects of high-dose caffeine (CAF) administration in pregnant rats upon the fetal hippocampus. MATERIALS AND METHODS: A total of 32 adult Wistar albino female rats were divided into four groups after conception (n = 8). At 9-20 days of pregnancy, intraperitoneal (i.p.) MEL was administered at a dose of 10 mg/kg/day in the MEL group, while i.p. CAF was administered at a dose of 60 mg/kg/day in the CAF group. In the CAF plus MEL group, i.p. CAF and MEL were administered at a dose of 60 and 10 mg/kg/day, respectively, at the same period. Following extraction of the brains of the fetuses sacrificed on the 21st day of pregnancy, their hippocampal regions were analyzed by hematoxylin and eosin and Cresyl Echt Violet, anti-GFAP, and antisynaptophysin staining methods. RESULTS: While there was a decrease in fetal and brain weights in the CAF group, it was found that the CAF plus MEL group had a closer weight average to that of the control group. Histologically, it was observed that the pyramidal cell layer consisted of 8-10 layers of cells due to the delay in migration in hippocampal neurons in the CAF group, while the MEL group showed similar characteristics with the control group. It was found that these findings decreased in the CAF plus MEL group. CONCLUSION: It is concluded that high-dose CAF administration causes a delay in neurogenesis of the fetal hippocampus, and exogenous MEL is able to mitigate its deleterious effects.

A neoteric annotation on the advances in combination therapy for Parkinson's disease: nanocarrier-based combination approach and future anticipation. Part II: nanocarrier design and development in focus.

INTRODUCTION: The current treatment modalities available for Parkinson's disease (PD) prove inadequate due to the inherent constraints in effectively transporting bioactive compounds across the blood-brain barrier. The utilization of synergistic combinations of multiple drugs in conjunction with advanced nanotechnology, emerges as a promising avenue for the treatment of PD, offering potential breakthroughs in treatment efficacy, targeted therapy, and personalized medicine. AREAS COVERED: This review provides a comprehensive analysis of the efficacy of multifactorial interventions for PD, simultaneously addressing the primary challenges of conventional therapies and highlighting how advanced technologies can help overcome these limitations. Part II focuses on the effectiveness of nanotechnology for improving pharmacokinetics of conventional therapies, through the synergistic use of dual or multiple therapeutic agents into a single nanoformulation. Significant emphasis is laid on the advancements toward innovative integrations, such as CRISPR/Cas9 with neuroprotective agents and stem cells, all effectively synergized with nanocarriers. EXPERT OPINION: By using drug combinations, we can leverage their combined effects to enhance treatment efficacy and mitigate side effects through lower dosages. This article is meant to give nanocarrier-mediated co-delivery of drugs and the strategic incorporation of CRISPR/Cas9, either as an independent intervention or synergized with a neuroprotective agent.