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 Uncoupling Effect of 17ß-Estradiol Underlies the Resilience of Female-Derived Mitochondria to Damage after Experimental TBI.

Current literature finds females have improved outcomes over their male counterparts after severe traumatic brain injury (TBI), while the opposite seems to be true for mild TBI. This begs the question as to what may be driving these sex differences after TBI. Estrogen is thought to be neuroprotective in certain diseases, and its actions have been shown to influence mitochondrial function. Mitochondrial impairment is a major hallmark of TBI, and interestingly, this dysfunction has been shown to be more severe in males than females after brain injury. This suggests estrogen could be playing a role in promoting "mitoprotection" following TBI. Despite the existence of estrogen receptors in mitochondria, few studies have examined the direct role of estrogen on mitochondrial function, and no studies have explored this after TBI. We hypothesized ex vivo treatment of isolated mitochondria with 17ß-estradiol (E2) would improve mitochondrial function after experimental TBI in mice. Total mitochondria from the ipsilateral (injured) and contralateral (control) cortices of male and female mice were isolated 24 h post-controlled severe cortical impact (CCI) and treated with vehicle, 2 nM E2, or 20 nM E2 immediately before measuring reactive oxygen species (ROS) production, bioenergetics, electron transport chain complex (ETC) activities, and ß-oxidation of palmitoyl carnitine. Protein expression of oxidative phosphorylation (OXPHOS) complexes was also measured in these mitochondrial samples to determine whether this influenced functional outcomes with respect to sex or injury. While mitochondrial ROS production was affected by CCI in both sexes, there were other sex-specific patterns of mitochondrial injury 24 h following severe CCI. For instance, mitochondria from males were more susceptible to CCI-induced injury with respect to bioenergetics and ETC complex activities, whereas mitochondria from females showed only Complex II impairment and reduced ß-oxidation after injury. Neither concentration of E2 influenced ETC complex activities themselves, but 20 nM E2 appeared to uncouple mitochondria isolated from the contralateral cortex in both sexes, as well as the injured ipsilateral cortex of females. These studies highlight the significance of measuring mitochondrial dysfunction in both sexes after TBI and also shed light on another potential neuroprotective mechanism in which E2 may attenuate mitochondrial dysfunction after TBI in vivo.

The reprotoxic adverse side effects of neurogenic and neuroprotective drugs: current use of human organoid modeling as a potential alternative to preclinical models.

The management of neurological disorders heavily relies on neurotherapeutic drugs, but notable concerns exist regarding their possible negative effects on reproductive health. Traditional preclinical models often fail to accurately predict reprotoxicity, highlighting the need for more physiologically relevant systems. Organoid models represent a promising approach for concurrently studying neurotoxicity and reprotoxicity, providing insights into the complex interplay between neurotherapeutic drugs and reproductive systems. Herein, we have examined the molecular mechanisms underlying neurotherapeutic drug-induced reprotoxicity and discussed experimental findings from case studies. Additionally, we explore the utility of organoid models in elucidating the reproductive complications of neurodrug exposure. Have discussed the principles of organoid models, highlighting their ability to recapitulate neurodevelopmental processes and simulate drug-induced toxicity in a controlled environment. Challenges and future perspectives in the field have been addressed with a focus on advancing organoid technologies to improve reprotoxicity assessment and enhance drug safety screening. This review underscores the importance of organoid models in unraveling the complex relationship between neurotherapeutic drugs and reproductive health.

A neurotherapeutic approach with Lacticaseibacillus rhamnosus E9 on gut microbiota and intestinal barrier in MPTP-induced mouse model of Parkinson's disease.

The gut microbiota plays a crucial role in neural development and progression of neural disorders like Parkinson's disease (PD). Probiotics have been suggested to impact neurodegenerative diseases via gut-brain axis. This study aims to investigate the therapeutic potential of Lacticaseibacillus rhamnosus E9, a high exopolysaccharide producer, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of PD. C57BL/6 mice subjected to MPTP were fed L. rhamnosus E9 for fifteen days and sacrificed after the last administration. Motor functions were determined by open-field, catalepsy, and wire-hanging tests. The ileum and the brain tissues were collected for ELISA, qPCR, and immunohistochemistry analyses. The cecum content was obtained for microbiota analysis. E9 supplementation alleviated MPTP-induced motor dysfunctions accompanied by decreased levels of striatal TH and dopamine. E9 also reduced the level of ROS in the striatum and decreased the DAT expression while increasing the DR1. Furthermore, E9 improved intestinal integrity by enhancing ZO-1 and Occludin levels and reversed the dysbiosis of the gut microbiota induced by MPTP. In conclusion, E9 supplementation improved the MPTP-induced motor deficits and neural damage as well as intestinal barrier by modulating the gut microbiota in PD mice. These findings suggest that E9 supplementation holds therapeutic potential in managing PD through the gut-brain axis.

Exosome-Based Macromolecular neurotherapeutic drug delivery approaches in overcoming the Blood-Brain barrier for treating brain disorders.

Delivering drugs to the brain is a complex challenge in medical research, particularly for disorders like Alzheimer's and Parkinson's. The blood-brain barrier restricts the entry of many therapeutic molecules, hindering their effectiveness. Nanoparticles, a potential solution, face issues like toxicity and limited approvals. A new avenue explores the use of small extracellular vesicles (sEVs), i.e., exosomes, as natural carriers for drug delivery. sEVs, tiny structures below 150 nm, show promise due to their minimal immune response and ability to precisely deliver drugs. This review focuses on the potential of sEVs-based drug delivery systems for treating neurological disorders, brain cancers, and other brain-related issues. Notably, bioengineered sEVs-carrying therapeutic compounds exhibit promise in early studies. The unique features of sEVs, such as their small size and natural properties, position them as candidates to overcome challenges in drug delivery to the brain. Ongoing clinical trials and research into sEVs behavior within the body further highlight their potential for revolutionizing drug delivery and addressing complex brain conditions.

Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders.

The oxytosis/ferroptosis regulated cell death pathway is an emerging field of research owing to its pathophysiological relevance to a wide range of neurological disorders, including Alzheimer's and Parkinson's diseases and traumatic brain injury. Developing novel neurotherapeutics to inhibit oxytosis/ferroptosis offers exciting opportunities for the treatment of these and other neurological diseases. Previously, we discovered cannabinol (CBN) as a unique, potent inhibitor of oxytosis/ferroptosis by targeting mitochondria and modulating their function in neuronal cells. To further elucidate which key pharmacophores and chemical space are essential to the beneficial effects of CBN, we herein introduce a fragment-based drug discovery strategy in conjunction with cell-based phenotypic screens using oxytosis/ferroptosis to determine the structure-activity relationship of CBN. The resulting information led to the development of four new CBN analogs, CP1-CP4, that not only preserve the sub-micromolar potency of neuroprotection and mitochondria-modulating activities seen with CBN in neuronal cell models but also have better druglike properties. Moreover, compared to CBN, the analog CP1 shows improved in vivo efficacy in the Drosophila model of mild traumatic brain injury. Together these studies identify the key molecular scaffolds of cannabinoids that contribute to neuroprotection against oxytosis/ferroptosis. They also highlight the advantageous approach of combining in vitro cell-based assays and rapid in vivo studies using Drosophila models for evaluating new therapeutic compounds.

Comparing Taste Perception Across Modalities in Healthy Adults: Liquids Versus Dissolvable Taste Strips.

Taste stimulation has rehabilitative value in dysphagia management, as it activates salient underlying afferent pathways to swallowing which may evoke feedforward effects on swallow biomechanics. Despite its potential beneficial effects on swallow physiology, taste stimulation's clinical application is limited for persons unsafe to orally consume food/liquid. This study aimed to create edible, dissolvable taste strips matched to flavor profiles previously used in research assessing taste's effects on swallowing physiology and brain activity, and to evaluate how similar their perceived intensity and hedonic, or palatability, ratings were between their liquid counterparts. Plain, sour, sweet-sour, lemon, and orange flavor profiles were custom-made in taste strips and liquid modalities. The generalized Labeled Magnitude Scale and hedonic generalized Labeled Magnitude Scale were used to assess intensity and palatability ratings for flavor profiles in each modality. Healthy participants were recruited and stratified across age and sex. Liquids were rated as more intense than taste strips; however, there was no difference in palatability ratings between the modalities. There were significant differences across flavor profiles in intensity and palatability ratings. Collapsed across liquid and taste strip modalities, pairwise comparisons revealed all flavored stimuli were rated as more intense than the plain profile, sour was perceived as more intense and less palatable than all other profiles, and orange was rated as more palatable than sour, lemon, and plain tastants. Taste strips have useful implications for dysphagia management, as they could offer safe and patient-preferred flavor profiles to potentially provide advantageous swallowing and neural hemodynamic responses.

Validating the Safe and Effective Use of a Neurorehabilitation System (InTandem) to Improve Walking in the Chronic Stroke Population: Usability Study.

BACKGROUND: Persistent walking impairment following a stroke is common. Although rehabilitative interventions exist, few exist for use at home in the chronic phase of stroke recovery. InTandem (MedRhythms, Inc) is a neurorehabilitation system intended to improve walking and community ambulation in adults with chronic stroke walking impairment. OBJECTIVE: Using design best practices and human factors engineering principles, the research presented here was conducted to validate the safe and effective use of InTandem. METHODS: In total, 15 participants in the chronic phase of stroke recovery (≥6 months after stroke) participated in this validation study. Participants were scored on 8 simulated use tasks, 4 knowledge assessments, and 7 comprehension assessments in a simulated home environment. The number and types of use errors, close calls, and operational difficulties were evaluated. Analyses of task performances, participant behaviors, and follow-up interviews were conducted to determine the root cause of use errors and difficulties. RESULTS: During this validation study, 93% (14/15) of participants were able to successfully complete the critical tasks associated with the simulated use of the InTandem system. Following simulated use task assessments, participants' knowledge and comprehension of the instructions for use and key safety information were evaluated. Overall, participants were able to find and correctly interpret information in the materials in order to answer the knowledge assessment questions. During the comprehension assessment, participants understood warning statements associated with critical tasks presented in the instructions for use. Across the entire study, 3 "use errors" and 1 "success with difficulty" were recorded. No adverse events, including slips, trips, or falls, occurred in this study. CONCLUSIONS: In this validation study, people in the chronic phase of stroke recovery were able to safely and effectively use InTandem in the intended use environment. This validation study contributes to the overall understanding of residual use-related risks of InTandem in consideration of the established benefits.

Morphological screens using aged primary adult neuronal, microglial, and astrocytic cultures to find novel neurotherapeutics.

The average age of a patient with neurotraumatic injuries or neurodegenerative diseases has been increasing worldwide. The preclinical live animal models used for neurotrauma and neurodegenerative diseases are typically young adults, failing to represent the age of humans in the clinic. This dichotomy in age between human populations and animal models is likely to impede the understanding of the pathological mechanisms of most neurological disorders and the translation of their respective promising therapies. This lack of cohesion between animal models and patients in the clinic begins prior to in vivo testing, it starts during the in vitro drug screening phase. Conventional screening methods typically involve the use of stem cell derived neural cells, with some researchers using embryonic derived neural cells instead. These cells lack the fundamental characteristics present in aged neural cells, such as age-induced changes in process length and branching in microglia and how astrocytes respond to various insults. Various technologies and techniques have been developed recently that can help researchers use age-appropriate neural cells for their drug discovery endeavors. The use of age-appropriate neural cells during screening phases is hypothesized to significantly increase the translation rate of the hits to the geriatric patients suffering from neurotraumatic and neurodegenerative diseases.

Therapeutic Potential of "Smart" Exosomes in Peripheral Nerve Regeneration.

Peripheral nerve injury results in severe loss of motor and sensory function in the affected limb. The gold standard for peripheral nerve repair is autologous nerve grafts, but their inherent drawbacks limit their use. Satisfactory clinical data are yet to be obtained using tissue engineered nerve grafts with neurotrophic factors introduced in these grafts for nerve repair. Therefore, peripheral nerve regeneration still remains a challenge for clinicians. Exosomes are secreted nanovesicles from the extracellular membrane. They are critical for communication within the cell and play a crucial role in the pathologic process of the peripheral nervous system. Recent research supports the role of exosomes in exhibiting neurotherapeutic effects through axonal growth, Schwann cell activation, and regulating inflammation. Indeed, the use of "smart" exosomes by reprogramming or manipulating the secretome contents and functions are rising as a therapeutic option for treating peripheral nerve defects. This review provides an overview on the promising role of exosomes in the process of peripheral nerve regeneration.

Case report: The gait deviation index may predict neurotherapeutic effects of FES-assisted gait training in children with cerebral palsy.

Background: Children with cerebral palsy (CP) show progressive loss of ambulatory function characterized by kinematic deviations at the hip, knee, and ankle. Functional electrical stimulation (FES) can lead to more typical lower limb kinematics during walking by eliciting appropriately timed muscle contractions. FES-assisted walking interventions have shown mixed to positive results in improving lower limb kinematics through immediate correction of gait during the application of FES, or long-term, persisting effects of non-FES-assisted gait improvements following multi-week FES-assisted gait training, at the absence of stimulation, i.e., neurotherapeutic effects. It is unknown, however, if children with CP will demonstrate a neurotherapeutic response following FES-assisted gait training because of the CP population's heterogeneity in gait deviations and responses to FES. Identifying the neurotherapeutic responders is, therefore, important to optimize the training interventions to those that have higher probability of benefiting from the intervention. Objective: The purpose of this case study was to investigate the relationship between immediate and neurotherapeutic effects of FES-assisted walking to identify responders to a FES-assisted gait training protocol. Methods: The primary outcome was Gait Deviation Index (GDI) and secondary outcome was root mean squared error (RMSE) of the lower extremity joint angles in the sagittal plane between participants with CP and a typically developing (TD) dataset. Potential indicators were defined as immediate improvements from baseline during FES-assisted walking followed by neurotherapeutic improvements at the end of training. Case description: Gait analysis of two adolescent female participants with spastic diplegia (Gross Motor Function Classification System level II and III) was conducted at the start and end of a 12-week FES-assisted treadmill training protocol. Participant 1 had scissoring crouch gait, while participant 2 had jump gait. Outcomes: The GDI showed both immediate (presence of FES) and neurotherapeutic (absence of FES after training period) improvements from baseline in our two participants. Joint angle RMSE showed mixed trends between immediate and neurotherapeutic changes from baseline. The GDI warrants investigation in a larger sample to determine if it can be used to identify responders to FES-assisted gait training.

Durability of Improved Trunk Control Following Activity-Based Locomotor Training in Children With Acquired Spinal Cord Injuries.

BACKGROUND: A recent study in pediatric spinal cord injury (SCI) demonstrated activity-based locomotor training (ABLT) improved trunk control, measured by the Segmental Assessment of Trunk Control (SATCo). It is not known whether improved trunk control is maintained and, if so, for how long. OBJECTIVES: The purpose was to determine the durability of improvements in trunk control after ABLT is stopped. We hypothesized that SATCo scores at follow-up would not significantly regress (a) beyond the score measured at discharge and (b) to the initial SATCo pre-ABLT level. METHODS: Patients were assessed pre ABLT, after completing an episode of care, and upon returning to the clinic 1 or more months without ABLT. Durability is a score change less than 3, which is the measurement error of the SATCo. RESULTS: Twenty-eight children (10 females; 4 ± 2.5 years old) completed at least 40 sessions of ABLT and returned for the follow-up 8 ± 7 months (range, 1-38) after the episode of care. Trunk control improved 6 ± 3/20 points with ABLT (p < .0001). At the follow-up, average SATCo score decreased 2 ± 2/20 points, and the follow-up SATCo score was 4 ± 3 points higher than pre ABLT (p < .0001). There was no correlation between the change in SATCo scores and changes in age, weight, height or elapsed time between discharge and follow-up. CONCLUSION: Improvements in trunk control due to ABLT were maintained, indicating ABLT is neurotherapeutic. Although not achieving complete recovery of trunk control, the immediate effects and sustained improvements provide support for a clinical shift to neurotherapeutic approaches and for continued research to achieve enhanced recovery.

Cerebellar Theta Burst Stimulation on Walking Function in Stroke Patients: A Randomized Clinical Trial.

Objectives: The objective of this study was to explore the efficacy of cerebellar intermittent theta burst stimulation (iTBS) on the walking function of stroke patients. Methods: Stroke patients with walking dysfunction aged 25-80 years who had suffered their first unilateral stroke were included. A total of 36 patients [mean (SD) age, 53 (7.93) years; 10 women (28%)] were enrolled in the study. All participants received the same conventional physical therapy, including transfer, balance, and ambulation training, during admission for 50 min per day during 2 weeks (10 sessions). Every session was preceded by 3 min procedure of cerebellar iTBS applyed over the contralesional cerebellum in the intervention group or by a similar sham iTBS in control group. The groups were formed randomly and the baseline characteristics showed no significant difference. The primary outcome measure was Fugl-Meyer Assessment-Lower Extremity scores. Secondary outcomes included walking performance and corticospinal excitability. Measures were performed before the intervention beginning (T0), after the first (T1) and the second (T2) weeks. Results: The Fugl-Meyer Assessment for lower extremity scores slightly improved with time in both groups with no significant difference between the groups and over the time. The walking performance significantly improved with time and between group. Two-way mixed measures ANOVA showed that there was significant interaction between time and group in comfortable walking time (F 2,68 = 6.5242, P = 0.0080, η2 partial = 0.276, ε = 0.641), between-group comparisons revealed significant differences at T1 (P = 0.0072) and T2 (P = 0.0133). The statistical analysis of maximum walking time showed that there was significant interaction between time and groups (F 2,68 = 5.4354, P = 0.0115, η2 partial = 0.198, ε = 0.734). Compared with T0, the differences of maximum walking time between the two groups at T1 (P = 0.0227) and T2 (P = 0.0127) were statistically significant. However, both the Timed up and go test and functional ambulation category scale did not yield significant differences between groups (P > 0.05). Conclusion: Our results revealed that applying iTBS over the contralesional cerebellum paired with physical therapy could improve walking performance in patients after stroke, implying that cerebellar iTBS intervention may be a noninvasive strategy to promote walking function in these patients. This study was registered at ChiCTR, number ChiCTR1900026450.

Integrating in vitro disease models of the neurovascular unit into discovery and development of neurotherapeutics.

The blood-brain barrier (BBB) regulates the transport of small molecules, proteins, and cells between the bloodstream and the central nervous system (CNS). Brain microvascular endothelial cells work with other resident brain cell types, including pericytes, astrocytes, neurons, and microglia, to form the neurovascular unit (NVU) and maintain BBB integrity. The restrictive barrier influences the pathogenesis of many CNS diseases, and impedes the delivery of neurotherapeutics into the CNS. In vitro NVU models enable the discovery of complex cell-cell interactions involved in human BBB pathophysiology in diseases including Alzheimer's Disease (AD), Parkinson's Disease (PD) and viral infections of the brain. In vitro NVU models have also been deployed to study the delivery of neurotherapeutics across the BBB, including small molecule drugs, monoclonal antibodies, gene therapy vectors and immune cells. The high scalability, accessibility, and phenotype fidelity of in vitro NVU models can facilitate the discovery and development of effective neurotherapeutics.

Use of Antioxidants for the Neuro-Therapeutic Management of COVID-19.

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is an emergent infectious disease that has caused millions of deaths throughout the world. COVID-19 infection's main symptoms are fever, cough, fatigue, and neurological manifestations such as headache, myalgias, anosmia, ageusia, impaired consciousness, seizures, and even neuromuscular junctions' disorders. In addition, it is known that this disease causes a series of systemic complications such as adverse respiratory distress syndrome, cardiac injury, acute kidney injury, and liver dysfunction. Due to the neurological symptoms associated with COVID-19, damage in the central nervous system has been suggested as well as the neuroinvasive potential of SARS-CoV-2. It is known that CoV infections are associated with an inflammation process related to the imbalance of the antioxidant system; cellular changes caused by oxidative stress contribute to brain tissue damage. Although anti-COVID-19 vaccines are under development, there is no specific treatment for COVID-19 and its clinical manifestations and complications; only supportive treatments with immunomodulators, anti-vascular endothelial growth factors, modulating drugs, statins, or nutritional supplements have been used. In the present work, we analyzed the potential of antioxidants as adjuvants for the treatment of COVID-19 and specifically their possible role in preventing or decreasing the neurological manifestations and neurological complications present in the disease.

Prediction of Drug Permeability Using In Vitro Blood-Brain Barrier Models with Human Induced Pluripotent Stem Cell-Derived Brain Microvascular Endothelial Cells.

The strong barrier function of the blood-brain barrier (BBB) protects the central nervous system (CNS) from xenobiotic substances, while the expression of selective transporters controls the transportation of nutrients between the blood and brain. As a result, the delivery of drugs to the CNS and prediction of the ability of specific drugs to penetrate the BBB can be difficult. Although in vivo pharmacokinetic analysis using rodents is a commonly used method for predicting human BBB permeability, novel in vitro BBB models, such as Transwell models, have been developed recently. Induced pluripotent stem cells (iPSCs) have the potential to differentiate into various types of cells, and protocols for the differentiation of iPSCs to generate brain microvascular endothelial cells (BMECs) have been reported. The use of iPSCs makes it easy to scale-up iPSC-derived BMECs (iBMECs) and enables production of BBB disease models by using iPSCs from multiple donors with disease, which are advantageous properties compared with models that utilize primary BMECs (pBMECs). There has been little research on the value of iBMECs for predicting BBB permeability. This study focused on the similarity of iBMECs to pBMECs and investigated the ability of iPSC-BBB models (monoculture and coculture) to predict in vivo human BBB permeability using iBMECs. iBMECs express BMEC markers (e.g., VE-cadherin and claudin-5) and influx/efflux transporters (e.g., Glut-1, SLC7A5, CD220, P-gp, ABCG2, and MRP-1) and exhibit high barrier function (transendothelial electrical resistance, >1000 Ω × cm2) as well as similar transporter expression profiles to pBMECs. We determined that the efflux activity using P-glycoprotein (P-gp) transporter is not sufficient in iBMECs, while in drug permeability tests, iPSC-derived BBB models showed a higher correlation with in vivo human BBB permeability compared with a rat BBB model and the Caco-2 model. In a comparison between monoculture and coculture models, the coculture BBB model showed higher efflux activity for compounds with low CNS permeability (e.g., verapamil and thioridazine). In conclusion, iPSC-BBB models make it possible to predict BBB permeability, and employing coculturing can improve iPSC-BBB function.

Personalized transcranial alternating current stimulation (tACS) and physical therapy to treat motor and cognitive symptoms in Parkinson's disease: A randomized cross-over trial.

Abnormal cortical oscillations are markers of Parkinson's Disease (PD). Transcranial alternating current stimulation (tACS) can modulate brain oscillations and possibly impact on behaviour. Mapping of cortical activity (prevalent oscillatory frequency and topographic scalp distribution) may provide a personalized neurotherapeutic target and guide non-invasive brain stimulation. This is a cross-over, double blinded, randomized trial. Electroencephalogram (EEG) from participants with PD referred to Specialist Clinic, University Hospital, were recorded. TACS frequency and electrode position were individually defined based on statistical comparison of EEG power spectra maps with normative data from our laboratory. Stimulation frequency was set according to the EEG band displaying higher power spectra (with beta excess on EEG map, tACS was set at 4 Hz; with theta excess, tACS was set at 30 Hz). Participants were randomized to tACS or random noise stimulation (RNS), 5 days/week for 2-weeks followed by ad hoc physical therapy. EEG, motor (Unified Parkinson's Disease Rating Scale-motor: UPDRS III), neuropsychological (frontal, executive and memory tests) performance and mood were measured before (T0), after (T1) and 4-weeks after treatment (T2). A linear model with random effects and Wilcoxon test were used to detect differences. Main results include a reduction of beta rhythm in theta-tACS vs. RNS group at T1 over right sensorimotor area (p = .014) and left parietal area (p = .010) and at T2 over right sensorimotor area (p = .004) and left frontal area (p = .039). Bradykinesia items improved at T1 (p = .002) and T2 (p = .047) compared to T0 in the tACS group. In the tACS group the Montréal Cognitive Assessment (MoCA) improved at T2 compared with T1 (p = .049). Individualized tACS in PD improves motor and cognitive performance. These changes are associated with a reduction of excessive fast EEG oscillations.

Resveratrol mitigates the oxidative stress mediated by hypoxic-ischemic brain injury in neonatal rats via Nrf2/HO-1 pathway.

CONTEXT: Hypoxic-ischemic encephalopathy (HIE) has a high morbidity and mortality rate. Resveratrol possesses numerous biological properties including antioxidant, anti-inflammatory and neuroprotective activities. OBJECTIVE: The current experiment investigates the neuroprotective efficacy of resveratrol (RESV) against HIE by modulating Nrf2/HO-1 pathway in neonatal rats. MATERIALS AND METHODS: Seven-day-old pups (n = 48) were divided into four groups. Group-I rats receiving 2% DMSO saline (sham), group-II rats underwent unilateral carotid artery ligation and hypoxia (92% N2 and 8% O2) for 2.5 h (hypoxia-ischemia; HI), group-III and IV rats received 20 (RESV 20 + HI) or 40 mg/kg (RESV 40 + HI; group-IV) of RESV via intraperitoneal injection (ip), respectively, for 7 days prior to HI induction. RESULTS: Pre-treatment with RESV (20 or 40) markedly reduced (p < 0.01) the cerebral oedema (86.23-71.26 or 65.24%), infarct area (33.85-19.81 or 14.30%), lipid peroxidation products, inflammatory markers [IL-1ß 186-110 or 82; IL-6 255-146 or 103; TNF-α 310-204 or 137; NF-κB 205-115 or 91) p65 subunit] and significantly restored (p < 0.01) the antioxidative status by enhancing the activities of glutathione peroxidase (GPx) 5.22-6.49 or 7.78; catalase (CAT) 51-55 or 59, superoxide dismutase (SOD) 2.5-3.05 or 3.25; through marked upregulation (p < 0.01) of heme oxygenase 1 (HO-1) 0.65-0.69 or 0.73; and nuclear factor erythroid 2 related factor 2 (Nrf2) 0.73-0.86 or 0.91. DISCUSSION AND CONCLUSIONS: RESV displays its neurotherapeutic potential via upregulating the protein expression of Nrf2 and HO-1 signalling pathway and thereby attenuates oxidative stress and inflammatory response in HI-induced neonatal rats.