Zuranolone therapy protects frontal cortex neurodevelopment and improves behavioral outcomes after preterm birth.

BACKGROUND: Preterm birth is associated with brain injury and long-term behavioral abnormalities, for which there are limited prevention options. When born preterm, infants prematurely lose placental neurosteroid (allopregnanolone) support. This increases the risk of excitotoxic damage to the brain, which increases the risk of injury, causing long-term deficits in behavior, myelination, and alterations to neurotransmitter pathways. We propose that postnatal restoration of neurosteroid action through zuranolone therapy will reduce neurological impairments following preterm birth. METHODS: Guinea pig dams underwent survival cesarean section surgery to deliver pups prematurely (GA64) or at term (GA69). Between birth and term equivalence age, preterm pups received vehicle (15% ß-cyclodextrin) or the allopregnanolone analogue zuranolone (1 mg/kg/day). Behavioral analysis was performed at postnatal day (PND) 7 and 40, before tissue collection at PND 42. Immunostaining for myelin basic protein (MBP), as well as real-time polymerase chain reaction to characterize oligodendrocyte lineage and neurotransmitter pathways, was performed in frontal cortex tissues. RESULTS: Zuranolone treatment prevented the hyperactive phenotype in preterm-born offspring, most markedly in males. Additionally, preterm-related reductions in MBP were ameliorated. Several preterm-related alterations in mRNA expression of dopaminergic, glutamatergic, and GABAergic pathways were also restored back to that of a term control level. CONCLUSION: This is the first study to assess zuranolone treatment as a neuroprotective therapy following preterm birth. Zuranolone treatment improved behavioral outcomes and structural changes in the preterm offspring, which continued long term until at least a late childhood timepoint. Clinical studies are warranted for further exploring the neuroprotective possibilities of this treatment following preterm birth.

Microenvironment-responsive nanosystems for ischemic stroke therapy.

Ischemic stroke, a common neurological disorder caused by impaired blood supply to the brain, presents a therapeutic challenge. Conventional treatments like thrombolysis and neuroprotection drugs lack ideal drug delivery systems, limiting their effectiveness. Selectively delivering therapies to the ischemic cerebral tissue holds great potential for preventing and/or treating ischemia-related pathological symptoms. The unique pathological microenvironment of the brain after ischemic stroke, characterized by hypoxia, acidity, and inflammation, offers new possibilities for targeted drug delivery. Pathological microenvironment-responsive nanosystems, extensively investigated in tumors with hypoxia-responsive systems as an example, could also respond to the ischemic cerebral microenvironment and achieve brain-targeted drug delivery and release. These emerging nanosystems are gaining traction for ischemic stroke treatment. In this review, we expound on the cerebral pathological microenvironment and clinical treatment strategies of ischemic stroke, highlight various stimulus-responsive materials employed in constructing ischemic stroke microenvironment-responsive nano delivery systems, and discuss the application of these microenvironment-responsive nanosystems in microenvironment regulation for ischemic stroke treatment.

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

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

Neuroprotective effects of salvianolic acids combined with Panax notoginseng saponins in cerebral ischemia/reperfusion rats concerning the neurovascular unit and trophic coupling.

BACKGROUND: The neurovascular unit (NVU) and neurovascular trophic coupling (NVTC) play a key regulatory role in brain injury caused by ischemic stroke. Salvianolic acids (SAL) and Panax notoginseng saponins (PNS) are widely used in China to manage ischemic stroke. Neuroprotective effects of SAL and PNS, either taken alone or in combination, were examined in this research. METHODS: Wistar rats were randomly divided into the following groups: Sham group (Sham), cerebral ischemia/reperfusion group (I/R), I/R with SAL group (SAL), I/R with PNS group (PNS), I/R with SAL combined with PNS (SAL + PNS), and I/R with edaravone group (EDA). Treatment was administered once daily for two days after modeling of middle cerebral artery occlusion/reperfusion (MCAO/R). RESULTS: Compared with the I/R group, SAL, PNS, or SAL + PNS treatment reduced infarct size, improved neurological deficit score, reduced Evans blue extravasation, increased expression of CD31 and tight junction proteins (TJs), including zonula occludens-1 (ZO-1), zonula occludens-2 (ZO-2), and junctional adhesion molecule-1 (JAM-1). Furthermore, SAL, PNS, or SAL + PNS suppressed the activations of microglia and astrocyte and led to the amelioration of neuron and pericyte injury. Treatment also inhibited NVU dissociation of GFAP/PDGFRß and Collagen IV/GFAP while upregulated the expression level of BDNF/TrkB and BDNF/NeuN. CONCLUSIONS: SAL and PNS have significantly remedied structural and functional disorders of NVU and NVTC in I/R injury. These effects were more pronounced when SAL and PNS were combined than when used separately.

Neuroprotective effects of intranasal extracellular vesicles from human platelet concentrates supernatants in traumatic brain injury and Parkinson's disease models.

BACKGROUND: The burgeoning field of regenerative medicine has significantly advanced with recent findings on biotherapies using human platelet lysates (HPLs), derived from clinical-grade platelet concentrates (PCs), for treating brain disorders. These developments have opened new translational research avenues to explore the neuroprotective effects of platelet-extracellular vesicles (PEVs). Their potential in managing neurodegenerative conditions like traumatic brain injury (TBI) and Parkinson's disease (PD) warrants further exploration. We aimed here to characterize the composition of a PEV preparation isolated from platelet concentrate (PC) supernatant, and determine its neuroprotective potential and neurorestorative effects in cellular and animal models of TBI and PD. METHODS: We isolated PEVs from the supernatant of clinical-grade PC collected from healthy blood donors utilizing high-speed centrifugation. PEVs were characterized by biophysical, biochemical, microscopic, and LC-MS/MS proteomics methods to unveil biological functions. Their functionality was assessed in vitro using SH-SY5Y neuronal cells, LUHMES dopaminergic neurons, and BV-2 microglial cells, and in vivo by intranasal administration in a controlled cortical impact (CCI)-TBI model using 8-weeks-old male C57/BL6 mice, and in a PD model induced by MPTP in 5-month-old male C57/BL6 mice. RESULTS: PEVs varied in size from 50 to 350 nm, predominantly around 200 nm, with concentrations ranging between 1010 and 1011/mL. They expressed specific platelet membrane markers, exhibited a lipid bilayer by cryo-electron microscopy and, importantly, showed low expression of pro-coagulant phosphatidylserine. LC-MS/MS indicated a rich composition of trophic factors, including neurotrophins, anti-inflammatory agents, neurotransmitters, and antioxidants, unveiling their multifaceted biological functions. PEVs aided in the restoration of neuronal functions in SH-SY5Y cells and demonstrated remarkable neuroprotective capabilities against erastin-induced ferroptosis in dopaminergic neurons. In microglial cells, they promoted anti-inflammatory responses, particularly under inflammatory conditions. In vivo, intranasally delivered PEVs showed strong anti-inflammatory effects in a TBI mouse model and conserved tyrosine hydroxylase expression of dopaminergic neurons of the substantia nigra in a PD model, leading to improved motor function. CONCLUSIONS: The potential of PEV-based therapies in neuroprotection opens new therapeutic avenues for neurodegenerative disorders. The study advocates for clinical trials to establish the efficacy of PEV-based biotherapies in neuroregenerative medicine.

Angiopep-2 conjugated biomimetic nano-delivery system loaded with resveratrol for the treatment of methamphetamine addiction.

Methamphetamine (METH) addiction can damage the central nervous system, resulting in cognitive impairment and memory deficits. Low target effects have limited the utility of anti-addiction drugs because the presence of the blood-brain barrier hinders the effective delivery of drugs to the brain. Angiopep-2 can recognize and target low-density lipoprotein receptor-associated protein 1 (LRP-1) on the surface of cerebral capillary endothelial cells, causing cross-cell phagocytosis, and thus has high blood-brain barrier transport capacity. Resveratrol (RSV) has been found to be a neuroprotective agent in many nervous system diseases. In our study, we modified Angiopep-2 on the surface of the erythrocyte membrane to obtain a modified erythrocyte membrane (Ang-RBCm) and coated RSV-loaded poly(ε-caprolactone)-poly(ethylene glycol) (PCL-PEG) nanoparticles with Ang-RBCm (Ang-RBCm@RSVNPs) to treat METH addiction. Our results showed that Ang-RBCm@RSVNPs can penetrate the blood-brain barrier and accumulate in the brain better than free RSV. Besides, mice treatetd with Ang-RBCm@RSVNPs showed less preference to METH-paired chamber and no noticeable tissue toxicity or abnormality was found in H&E staining images. Electrophysiological experiments demonstrated Ang-RBCm@RSVNPs could elevate synaptic plasticity impaired by METH. These indicated that Ang-RBCm@RSVNPs has better anti-addiction and neuroprotective effects. Therefore, Ang-RBCm@RSVNPs has great potential in the treatment of METH addiction.

Pegylated chitosan nanoparticles of fluoxetine enhance cognitive performance and hippocampal brain derived neurotrophic factor levels in a rat model of local demyelination.

Cognitive impairment is a common feature in neurodegenerative diseases such as multiple sclerosis (MS). This study aims to explore the potential of enhancing the beneficial effects of fluoxetine (FLX), a neuroprotective agent known for its ability to increase neural plasticity by utilizing nanoparticles. The study specifically focuses on the synthesis and evaluation of PEGylated chitosan nanoparticles of FLX and its effect on demyelination and the subsequent cognitive impairment (CI) in the hippocampus of rats induced by local injection of lysophosphatidylcholine (LPC). Chitosan/polyethylene glycol nanoparticles were synthesized, and their properties were analyzed. Demyelination was induced in rats via hippocampal injections of lysolecithin. Behavioral assessments included open field maze, elevated plus maze, and novel object recognition memory (NORM) tests. Hippocampal levels of insulin-like growth factor (IGF-1) and brain-derived neurotrophic factor (BDNF) were measured using enzyme-linked immunoassay (ELISA). The extent of remyelination was quantified using Luxol fast blue staining. Nanoparticle size measured 240.2 nm with 53 % encapsulation efficacy. Drug release exhibited a slow pattern, with 76 % released within 4 h. Nanoparticle-treated rats displayed reduced anxiety-like behavior, improved memory, increased BDNF levels, and a reduced extent of demyelination, with no change in IGF- levels. In addition, FLX -loaded chitosan nanoparticles had better effect on cognitive improvement, BDNF levels in the hippocampus that FLX. Altering pharmacokinetics and possibly pharmacodynamics. These findings highlight the potential of innovative drug delivery systems, encouraging further research in this direction.

Evaluation of the Regeneration Effects of Systemically Applied Methylprednisolone and Vitamin B12 on Mental Nerve Crush Injury.

AIM: To evaluate the effects of methylprednisolone and vitamin B12 injection on the regeneration of the nerves after a mental nerve crush injury. MATERIAL AND METHODS: A total of 40 albino Wistar rats have been randomly divided into four groups: group 1 (n=10): crushlike nerve damage was created by pinching the left mental nerve for 60 s with an aneurysm clip and intraperitoneally administered 1 ml of saline for 14 days; group 2 (n=10): the left mental nerve was pinched for 60 s with an aneurysm clip and intraperitoneally administered 2 mg/kg of methylprednisolone for 14 days; group 3, experimental group (n=10): the left mental nerve was pinched for 60 s with an aneurysm clip and intraperitoneally administered 2 mg/kg of vitamin B12 for 14 days; and group 4, experimental group (n=10): the left mental nerve was pinched for 60 s and intraperitoneally administered 2 mg/kg of methylprednisolone and 2 mg/kg of vitamin B12 for 14 days. All rats were sacrificed on the 28th postoperative day, and histopathological evaluation was performed. RESULTS: Nerve damage was higher in the control group than in other groups (p < 0.05). When Neural Cell Adhesion Molecule (NCAM) expression levels were compared, no major differences were observed between the methylprednisolone and control groups (p > 0.05). The B12 and B12+methylprednisolone groups reached significantly higher NCAM expression levels compared to the control and methylprednisolone groups. When the myelin basic protein (MBP) expression levels were compared (p < 0.05), the MBP expression was significantly higher in all experimental groups than in the control group (p < 0.05). CONCLUSION: Systemic vitamin B12 and methylprednisolone administration effectively supported remyelination in the crushed mental nerve by increasing Schwann cell proliferation and differentiation.

An oil-in-gel type of organohydrogel loaded with methylprednisolone for the treatment of secondary injuries following spinal cord traumas.

The secondary injuries following traumatic spinal cord injury (SCI) is a multiphasic and complex process that is difficult to treat. Although methylprednisolone (MP) is the only available pharmacological regime for SCI treatment, its efficacy remains controversial due to its very narrow therapeutic time window and safety concerns associated with high dosage. In this study, we have developed an oil-in-gel type of organohydrogel (OHG) in which the binary oleic-water phases coexist, for the local delivery of MP. This new OHG is fabricated by a glycol chitosan/oxidized hyaluronic acid hydrophilic network that is uniformly embedded with a biocompatible oil phase, and it can be effectively loaded with MP or other hydrophobic compounds. In addition to spatiotemporally control MP release, this biodegradable OHG also provides a brain tissue-mimicking scaffold that can promote tissue regeneration. OHG remarkably decreases the therapeutic dose of MP in animals and extends its treatment course over 21 d, thereby timely manipulating microglia/macrophages and their associated with signaling molecules to restore immune homeostasis, leading to a long-term functional improvement in a complete transection SCI rat model. Thus, this OHG represents a new type of gel for clinical treatment of secondary injuries in SCI.

Magnesium sulfate for fetal neuroprotection in preterm pregnancy: a meta-analysis of randomized controlled trials.

BACKGROUND: Intravenous administration of magnesium sulfate (MgSO4) to expectant individuals before childbirth, has been evaluated to reduce the likelihood of mortality and occurrence cerebral palsy in their offspring. Therefore, this systematic review and meta-analysis conducted to determine if were the prophylactic use of magnesium sulfate in women at risk for preterm delivery leads to decrease in the incidence of death or cerebral palsy. METHODS: A comprehensive search of electronic databases was done to identify relevant studies. Selection of eligible studies was based on predetermined inclusion criteria. Data extraction was performed, and the methodological quality of the selected studies was assessed using appropriate evaluative tools. A meta-analysis was carried out to estimate the overall effect of intravenous administration of magnesium sulfate on the incidence of death or cerebral palsy. RESULTS: A total of 7 studies met the inclusion criteria and were included in the final analysis. No significant publication bias was observed. The risk of fetal neurological impairment was significantly lower in the MgSO4 group compared to the control group relative risk (RR = 0.70, 95% CI: 0.56 to 0.87; I20%). However, neonatal mortality was not significantly associated with MgSO4 injection. (RR = 1.03, 95% CI: 0.88 to 1.21; I2 = 42%). Subgroup analysis was done based on the bolus dosage of MgSO4 and the duration of the trial follow-up. revealing a non-significant differences between-group. CONCLUSION: This study demonstrated that MgSO4 administration can improve fetal neurological impairment and cerebral palsy but is not linked to reducing mortality. Further studies are necessary to strengthen the evidence and clarify the underlying mechanisms.

[Place of oligopeptide H-Met-Glu-His-Phe-Pro-Gly-Pro-OH in the therapy and rehabilitation of patients with ischemic stroke]. / Mesto oligopeptida H-Met-Glu-His-Phe-Pro-Gly-Pro-OH v terapii i reabilitatsii patsientov s ishemicheskim insul'tom.

Cerebrovascular diseases (CVDs) are one of the leading causes of death and disability In Russia: they rank second in the structure of mortality from diseases of the circulatory system and in the overall mortality of the population. Successful treatment of CVD involves an integrated approach to the problem, taking into account the compensation of cardiovascular disorders, the elimination of neurological and psychopathological syndromes, the improvement of cerebral circulation and the use of neuroprotective agents that increase the resistance of brain tissue to hypoxia and ischemia. Insufficient clinical efficacy of neuroprotectors is due to a number of objective reasons, of which only two are universal. The first of these reasons is the timing of the start of therapy in the clinic, as a rule, is outside the «therapeutic window¼; the second reason is the fact that disturbance of the patency of the cerebral vessels in the affected area makes it difficult or impossible to deliver the drug to the penumbra area. The way out of this situation is the intranasal route of drug administration, which is characteristic for the analogs of regulatory peptides such as for H-Met-Glu-His-Phe-Pro-Gly-Pro-OH (MGHPPGP). The review of clinical studies indicates that MGHPPGP is clinically effective in the treatment of ischemic stroke both in the acute period of stroke and in the recovery period. The clinical efficacy of MGHPPGP was shown both in atherothrombotic and cardioembolic subtypes of stroke, against the background of blood flow disturbances in both the carotid and vertebrobasilar systems.

A combination of topical and systemic administration of brimonidine is neuroprotective in the murine optic nerve crush model.

Glaucoma is a multifactorial optic neuropathy that primarily affecting retinal ganglion cells (RGC). Brimonidine is an intraocular pressure-lowering drug with reported neuroprotective properties. This study aimed to compare the neuroprotective effects of topical and intraperitoneal (IP) brimonidine on RGCs from different retinal segments in a murine optic nerve crush (ONC) model. METHODS: forty-one Balb/c mice underwent unilateral ONC and were divided into three study groups: fifteen animals received saline drops twice per day and two additional IP injections of saline; fourteen mice received brimonidine drops twice per day; and 12 mice received brimonidine eye drops twice per day and two additional IP brimonidine injections. Animals were sacrificed seven days post-ONC, and immunohistochemical staining of retinal whole mounts was performed using neuronal NeuN and GFAP staining. Microscopic pictures of the central, middle, and peripheral regions of the retina were taken. The density of the retinal cells was assessed. RESULTS: The total RGC density after ONC and RGC densities in all retinal eccentricities were significantly higher in the brimonidine eye drop and IP combination treatment group than in the saline drop + saline IP, and brimonidine drop treatment groups. CONCLUSIONS: brimonidine eye drops supplemented with IP brimonidine injections improved RGC survival in a preclinical model of ONC.

A Preliminary Finding: N-butyl-phthalide Plays a Neuroprotective Role by Blocking the TLR4/HMGB1 Pathway and Improves Mild Cognitive Impairment Induced by Acute Cerebral Infarction.

BACKGROUND: Most acute cerebral infarctions (ACI) may develop vascular dementia (VD), which involves almost all types of cognitive impairment. Unfortunately, there is currently no effective treatment for VD. Most patients exhibit mild cognitive impairment (MCI) before the development of VD. N-butyl-phthalide (NBP) is used to treat ACI and improve cognitive function. The oxygen and glucose deprivation (OGD) model of neurons is an in vitro model of ischemia, hypoxia, and cognitive dysfunction. METHODS: We conducted clinical studies and in vitro experiments to investigate the clinical efficacy and mechanism of action of NBP for treating ACI-induced MCI. Patients with ACI-induced MCI were randomly divided into control (Ctrl) and NBP groups. We assessed various indicators, such as clinical efficacy, montreal cognitive assessment scale (MOCA), activities of daily living (ADL), and cerebral infarct size in both groups before and after treatment. We observed the morphology of neurons and detected the survival rate, action potentials (APs), expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), and the interaction between TLR4 and HMGB1. RESULTS: The MOCA and ADL scores increased significantly after treatment in the NBP group. A OGD model of neurons was established, and the neurons were divided into Ctrl and NBP groups. We observed that the survival rate and APs amplitude of the neurons were significantly increased in the NBP group, whereas TNF-α expression was decreased. Furthermore, the interaction between TLR4 and HMGB1 decreased in the NBP group. CONCLUSION: NBP plays a neuroprotective role by inhibiting the TLR4/HMGB1 pathway and ameliorating ACI-induced MCI.

Neurodevelopmental changes in Drosophila melanogaster are restored by treatment with lutein-loaded nanoparticles: Positive modulation of neurochemical and behavioral parameters.

Neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), are characterized by persistent changes in communication and social interaction, as well as restricted and stereotyped patterns of behavior. The complex etiology of these disorders possibly combines the effects of multiple genes and environmental factors. Hence, exposure to insecticides such as imidacloprid (IMI) has been used to replicate the changes observed in these disorders. Lutein is known for its anti-inflammatory and antioxidant properties and is associated with neuroprotective effects. Therefore, the aim of this study was to evaluate the protective effect of lutein-loaded nanoparticles, along with their mechanisms of action, on Drosophila melanogaster offspring exposed to IMI-induced damage. To simulate the neurodevelopmental disorder model, flies were exposed to a diet containing IMI for 7 days. Posteriorly, their offspring were exposed to a diet containing lutein-loaded nanoparticles for a period of 24 h, and male and female flies were subjected to behavioral and biochemical evaluations. Treatment with lutein-loaded nanoparticles reversed the parameters of hyperactivity, aggressiveness, social interaction, repetitive movements, and anxiety in the offspring of flies exposed to IMI. It also protected markers of oxidative stress and cell viability, in addition to preventing the reduction of Nrf2 and Shank3 immunoreactivity. These results demonstrate that the damage induced by exposure to IMI was restored through treatment with lutein-loaded nanoparticles, elucidating lutein's mechanisms of action as a therapeutic agent, which, after further studies, can become a co-adjuvant in the treatment of neurodevelopmental disorders, such as ASD and ADHD.

Intracerebroventricular administration of the exercise hormone irisin or acute strenuous exercise alleviates epileptic seizure-induced neuroinflammation and improves memory dysfunction in rats.

BACKGROUND: Status epilepticus is a common and potentially life-threatening neurological emergency with a high risk for cognitive and neurobiological impairment. Our aim was to evaluate the neuroprotective effects of centrally administered irisin and acute exhausting exercise against oxidative brain injury and memory dysfunction due to a pentylenetetrazole (PTZ)-induced single seizure. Male Sprague Dawley rats with intracerebroventricular (icv) cannulas were randomly divided into intraperitoneally (ip) saline-injected control and PTZ-injected (45 mg/kg) seizure groups. Both the control and PTZ groups were then treated with irisin (7.5 µg/kg, 2 µl, icv), saline (2 µl, icv) or were forced to an acute bout of strenuous exercise before the ip injection of saline (control) or PTZ. Seizures were evaluated using the Racine score. To evaluate memory performance, a passive avoidance test was performed before and after PTZ injection. Following euthanasia at the 24th hour of seizure induction, brain tissues were removed for histopathological examination and for evaluating oxidative damage, antioxidant capacity, and neurotransmitter levels. RESULTS: Glutamate/GABA imbalance observed in PTZ rats was corrected by irisin administration (p < 0.001/p < 0.01), while irisin prevented the generation of reactive oxygen species and lipid peroxidation (p < 0.05 - 0.001) and replenished the antioxidant catalase and glutathione levels (p < 0.01-0.01) in the cerebral tissue, and reduced the histologically evident neuronal injury due to a single seizure (p < 0.05 - 0.01). Irisin also delayed the onset of seizures (p < 0.05) and improved memory dysfunction (p < 0.05), but did not affect the severity of seizures. The acute exhaustive swimming exercise completed before PTZ-seizure depressed glutamate level (p < 0.001), maintained the oxidant/antioxidant balance, alleviated neuronal injury (p < 0.05 - 0.01) and upregulated cerebral BDNF expression (p < 0.05). CONCLUSION: In conclusion, acute high-intensity exercise or exogenously administered irisin provides neuroprotection by maintaining the balance of excitatory/inhibitory neurotransmitters and oxidant/antioxidant systems.

Emerging treatment landscape for Guillain-Barré Syndrome (GBS): what's new?

INTRODUCTION: Guillain-Barré syndrome (GBS) is a monophasic immune neuropathic disorder characterized by acute paralysis. A significant portion of patients are left with residual deficits, which presents a considerable global healthcare challenge. The precise mechanisms underlying GBS pathogenesis are not fully elucidated. Recent studies have focused on postinfectious molecular mimicry and identified involvement of IgG autoantibodies and innate immune effectors in GBS. Intravenous immunoglobulins (IVIg) and plasma exchange (PE) are two established evidence-based immunomodulatory treatments for GBS, but a significant proportion of GBS patients fails to respond adequately to either therapy. This emphasizes an urgent need for novel and more potent treatments. AREAS COVERED: We discuss novel immunomodulatory therapies presently at different phases of preclinical and clinical investigation. Some drugs in development target pathophysiologic mechanisms such as IgG autoantibody catabolism and complement activation, which are relevant to GBS. EXPERT OPINION: There is an unmet need for more effective immune therapies for GBS. New immunomodulatory therapies under development may provide more potent options for GBS patients who do not respond to IVIg or PE. Future directions may include incorporating neuroprotective interventions based on evolving understanding of mechanisms underlying nerve injury and axonal degeneration.

A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics. PATIENTS AND METHODS: This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28. FINDINGS: Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection. INTERPRETATION: Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS. TRIAL REGISTRATION: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.