Search

Background: A comprehensive approach to drug repositioning will be required to overcome translational hurdles and identify more neuroprotective drugs. Results & methods: Gene Set Enrichment Analysis was applied to identify related pathways and enriched genes. Candidate genes were optimized using ToppGene, ToppGenet and pBRIT. From the perspective of the local structures, gene–domain–substructure–drug relationships were constructed. Using the MCODE algorithm and K-means clustering, 31 functional subnetworks were obtained, and 252 drugs with proposed neuroprotective function were identified. Using computational analysis, 72 substructures with different scores were found to correspond to neuroprotective functions. The protective effects of benidipine and barnidipine were confirmed in vitro. Conclusion: The authors' research has great potential to discover more neuroprotective drugs and obtain more information regarding mechanisms of action and functional substructures.

Background There is an increasing of reports describing the efficacy of neuroprotective small molecule in Parkinson's disease (PD) models. Ideally, the choice of pushing drug candidates to clinical trial should be based on an unbiased assessment of all available data. Systematic review uses a methodical approach to minimize the bias in the selection of studies for inclusion, providing a comprehensive understanding of the drug's effects on multiple animal models with different mechanism. To our knowledge, such assessments of baicalein, which is a candidate neuroprotective drug with efficacy in PD, have not been fully conducted. Purpose To provide a comprehensive understanding of baicalein's effects on different animal models with different mechanism by using a methodical approach to minimize the bias in the selection of studies. Methods In this study, we used a systematic review method to comprehensively assess the efficacy of baicalein in animal PD models. By using electronic and manual search for the literatures, we identified studies describing the efficacy of baicalein in animal models of PD. Results We identified 16 studies describing the efficacy of baicalein in animal models of PD. The methodological quality of all preclinical trials is ranged from 2 to 5. 16 studies involved 4 main kinds of PD animal models. They are MPP+-induced, rotenone-induced, 6-OHDA-induced and acrolein-induced PD models, respectively. The protective effects of baicalein were studied mainly focusing on the anti-oxidative, anti-apoptotic, and anti-inflammatory action. Beyond that, there are 2 articles describing the effects of baicalein on neurotransmitter balance in the basal ganglia, and 2 articles reporting the effects in decreasing synuclein aggregation. Conclusions The results demonstrated the neuroprotective effects of baicalein in PD experimental animals and analyzed the pharmacological mechanism. The information will be useful for the further development of baicalein into anti-PD agent and provide unbiased evidence for the conduct of clinical trials. In addition, such evaluation based on animal experiments can give us a general introduction to different animal models of PD, either guiding the further model tests, or avoiding the unnecessary replication.

Introduction: Perinatal asphyxia is one of the leading causes of perinatal death and a recognized cause of neuromotor disability among survivors. About 20% - 30% of asphyxiated newborns who develop hypoxic ischemic encephalopathy (HIE) die during the neonatal period, and one third to one half of survivors are left with cerebral palsy and mental retardation. Objective of the Study: Was to determine the effect of magnesium sulphate as neuroprotective drug in hypoxic ischemic encephalopathy resulting from severe perinatal asphyxia. Materials and Methods: A prospective administration of magnesium sulphate to 52 severely asphyxiated newborns with hypoxic ischemic encephalopathy was conducted over one year period from 1st August 2017 to 31st July 2018. Results: Most (96.2%) of patients were term baby (GA ≥ 37 weeks). Most (90.4%) were in-hospital born, vaginal delivery accounted for 55.8% and 44.2% assisted delivery respectively. About one half (55.8%) of the patients commenced MgSO4 therapy at 24 hours after birth respectively. Time of commencement of first enteral feeding (p = 0.018) and time to full enteral feeding (p = 0.015) showed significant correlation with the survival without neurological deficit. The earlier the commencement of MgSO4 therapy, the better the proportion with strong palmar grasp, sucking reflex, tone and early resolution of encephalopathy. Conclusion: All the study subjects treated with magnesium sulphate had impressive improvement; however there is a need to conduct randomized placebo-controlled trial treatment of severe perinatal asphyxia so as to determine its effects on early resolution of hypoxic ischemic encephalopathy/neuroprotective activity.

DL-3-n-butylphthalide (NBP) is widely used as a neuroprotective drug for ischemic stroke in China. There is, however, no established evidence on its efficacy and safety for patients with ischemic stroke. We, therefore, conducted a systematic review and meta-analysis. Major databases were searched to identify randomized controlled trials that assessed the efficacy and safety of NBP on ischemic stroke, reporting outcomes among patients treated with NBP alone or combined with standard anti-ischemic stroke drugs vs. standard anti-ischemic stroke drugs. Continuous data were validated, extracted and synthesized of standardized mean differences (SMDs) by random effects models, while dichotomous data were validated, extracted and synthesized of relative risk (RR) by random effects models. Twelve randomized controlled trials involving 1160 patients were identified. Results suggested that NBP monotherapy is not superior to standard anti-ischemic stroke drugs based on the Barthel Index (SMD, 0.25; 95% CI [Formula: see text]0.14 to 0.63; [Formula: see text]) and the National Institutes of Health Stroke Scale (SMD, 0.73; 95% CI [Formula: see text]0.14 to 1.59; [Formula: see text]). In contrast, the combination of NBP and standard anti-ischemic stroke drugs appears to be superior to standard drugs alone, again based on both the Barthel index (SMD, 1.65; 95% CI 1.25 to 2.04; [Formula: see text]) and National Institutes of Health Stroke Scale (SMD, 1.40; 95% CI 0.72 to 2.09; [Formula: see text]). However, the use of NBP may cause adverse event on the function of the liver (RR, 3.55; 95% CI 1.19 to 10.56; [Formula: see text]). The combination use of NBP and standard anti-ischemic stroke drugs is more effective than standard drugs. However, more attention should be payed to the adverse effects on liver function. Our findings provided an established evidence of NBP as a neuroprotective drug, which may improve the current guideline for treatment of ischemic stroke.

Head injury is among the most devastating types of injury, specifically called Traumatic Brain Injury (TBI). There is a need to diminish the morbidity related with TBI and to improve the outcome of patients suffering TBI. Among the improvements in the treatment of TBI, neuroprotection is one of the upcoming improvements. Citicoline has been used in the management of brain ischemia related disorders, such as TBI. Citicoline has biochemical, pharmacological, and pharmacokinetic characteristics that make it a potentially useful neuroprotective drug for the management of TBI. A short review of these characteristics is included in this paper. Moreover, a narrative review of almost all the published or communicated studies performed with this drug in the management of patients with head injury is included. Based on the results obtained in these clinical studies, it is possible to conclude that citicoline is able to accelerate the recovery of consciousness and to improve the outcome of this kind of patient, with an excellent safety profile. Thus, citicoline could have a potential role in the management of TBI.

Simple Summary Ischemic stroke is caused by the blockade of a blood vessel in the brain. Consequently, the brain region supplied by the blocked vessel suffers brain damage and becomes acidic. Here we provide a summary of the causes and consequences of acid accumulation in the brain tissue. Ischemic stroke requires immediate medical attention to minimize the damage of brain tissue, and to save function. It would be desirable for the medical treatment to target the site of injury selectively, to enrich the site of ongoing injury with the protective agent, and to avoid undesirable side effects at the same time. We propose that acid accumulation at the sight of brain tissue injury can be used to delineate the region that would benefit most from medical treatment. Tiny drug carriers known as nanoparticles may be loaded with drugs that protect the brain tissue. These nanoparticles may be designed to release their drug cargo in response to an acidic environment. This would ensure that the therapeutic agent is directed selectively to the site where it is needed. Ultimately, this approach may offer a new way to treat stroke patients with the hope of more effective therapy, and better stroke outcome. Abstract Ischemic stroke is a leading cause of death and disability worldwide. Yet, the effective therapy of focal cerebral ischemia has been an unresolved challenge. We propose here that ischemic tissue acidosis, a sensitive metabolic indicator of injury progression in cerebral ischemia, can be harnessed for the targeted delivery of neuroprotective agents. Ischemic tissue acidosis, which represents the accumulation of lactic acid in malperfused brain tissue is significantly exacerbated by the recurrence of spreading depolarizations. Deepening acidosis itself activates specific ion channels to cause neurotoxic cellular Ca2+ accumulation and cytotoxic edema. These processes are thought to contribute to the loss of the ischemic penumbra. The unique metabolic status of the ischemic penumbra has been exploited to identify the penumbra zone with imaging tools. Importantly, acidosis in the ischemic penumbra may also be used to guide therapeutic intervention. Agents with neuroprotective promise are suggested here to be delivered selectively to the ischemic penumbra with pH-responsive smart nanosystems. The administered nanoparticels release their cargo in acidic tissue environment, which reliably delineates sites at risk of injury. Therefore, tissue pH-targeted drug delivery is expected to enrich sites of ongoing injury with the therapeutical agent, without the risk of unfavorable off-target effects.

The antioxidant-mediated neuroprotective effect of Allium cepa outer scale extract (ACE) in mice with cerebral ischemia-reperfusion (I-R) injury was demonstrated in our earlier work. The current investigation aimed at establishing the bioactive component(s) responsible for this activity. Thus ACE was fractionated into ethyl acetate (EF) and aqueous (AF) fractions. These fractions were evaluated against cerebral I-R injury in mice. I-R injury in mice was induced by bilateral common carotid artery occlusion followed by 24 hr reperfusion. Memory, sensorimotor functions, cerebral infarct size, and oxidative stress were measured to address the neuroprotective mechanism of test substances. EF showed marked improvement of memory and sensorimotor functions by reducing brain oxidative stress and infarct size in mice after I-R injury. The bioactive EF was subjected to chromatographic (HPLC-PDA, HPLC-MS, preparative HPLC) and spectroscopic studies to isolate and identify the neuroprotective compounds. This lead to separation of three components, namely quercetin, quercetin 4'-O-glucoside, and the remaining fraction, from EF. The separated components were biologically evaluated. These components showed improvement in mice with I-R injury. But, EF displayed more marked neuroprotective effects as compared to the isolated components. The distinct neuroprotective outcome of EF may be credited to the synergistic action of compounds present in EF. Further studies such as evaluation of neurotoxic effects and other possible neuroprotective mechanisms are required to develop EF as a neuroprotective drug.

We studied the dynamics in the state of cognitive function on the MMSE scale in young, middle-age and elderly patients after surgery under general anesthesia on the background of intensive neuroprotective therapy. The study was conducted in surgical departments of various profiles at the Kharkov City Clinical Hospital for Emergency and Emergency Medical Services named professor A.I. Meshchaninov. All patients underwent standard intravenous premedication. Surgery was performed under conditions of general multicomponent anesthesia with artificial lung ventilation using propofol and fentanyl, thiopental sodium and fentanyl. The dynamics of the state of cognitive function in patients after surgery using general anesthesia on the background of neuroprotective therapy were examined in 126 patients. Intensive neuroprotective drug was added to the patients on the background of standard postoperative therapy. The duration of the operation was (89,6±31,2) minutes, aged 18 to 80 years. Group 1 were 43 young patients (18–43 years old); mean age is (32,3±2,4) years, 24 men, 19 women. Group 2 were 41 middle-aged patients (44–59 years); mean age is (48,7±6,1) years, 19 males, 22 females. Group 3 were 42 elderly patients (60–80 years); mean age is (73,1±6,1) years, 20 males, 22 females. Thus, at 1st day after surgery, the results of the MMSE test values worsened significantly from the values before surgery. Significant impairment of test values was observed in patients of group 3 (14,2 % of values before surgery). As early as day 7, MMSE test scores improved significantly but did not fully recover in patients in group 3 (4,7 % of values before surgery). Patients in group 2 had better values before surgery by 1,8 %. During the month, the MMSE test scores improved significantly, in groups 2 and 3, they were higher before surgery (2,6 and 6,3 %, respectively in the groups). Less significant reductions in MMSE at day 1 were observed in patients in group 2 (5,5 % of values before surgery). In the data in patients of 2 groups the deterioration of the values of the test, which occurred after surgery, were quite likely renewed and improved by 7 days. Patients in group 1 had a slightly worse picture than patients in group 2, with 1 day results of MMSE significantly decreased by 8,4 % of values before surgery, but almost recovered by 7 days (3,8 % of values before operations) and improved by 0,3 % over the month prior to surgery. The deterioration of the MMSE test score from day 1 gradually recovered in each group, with improvements from up to operational values in all groups. MMSE test scores after surgery from the maximum possible result at 7 days (8,0; 8,0, and 19,6 %) and 1 month (4,6; 7,3, and 10,3 %) after surgery had a proportional age dependency and no age proportionality for 1 day. In patients of middle age on the background of neuroprotective therapy was observed dynamics of deterioration of cognitive function to a lesser extent, with faster recovery and improvement than in patients of young age, possibly due to age-related features of plasticity of cognitive function.

The use of neuroprotective agents for stroke is pathogenetically justified, but the translation of the results of preclinical studies of neuroprotectors into clinical practice has been a noticeable failure. One of the leading reasons for these failures is the one-target mechanism of their activity. p-Tyrosol (Tyr), a biophenol, is present in a variety of natural sources, mainly in foods, such as olive oil and wine. Tyr has a wide spectrum of biological activity: antioxidant, stress-protective, anti-inflammatory, anticancer, cardioprotective, neuroprotective and many others. This review analyzes data on the neuroprotective, antioxidant, anti-inflammatory, anti-apoptotic and other kinds of Tyr activity as well as data on the pharmacokinetics of the substance. The data presented in the review substantiate the acceptability of tyr as the basis for the development of a new neuroprotective drug with multitarget activity for the treatment of ischemic stroke. Tyr is a promising molecule for the development of an effective neuroprotective agent for use in ischemic stroke.

We aim to define a target population of stroke patients treated with EVT, in whom a potential neuroprotective (NP) drug has highest chances to show clinical and radiological positive effects. Methods: we studied stroke patients treated with EVT. CBF Results: We included 211 patients, mean FIV was 39(±58)cc and median dNIHSS 6(1-15). FIV strongly correlated to dNIHSS (rs=0.74; p Conclusion: One in 4 patients will develop minimal FIV, including these patients in NP trials may dilute a treatment effect and reduce odds of positive results. In large FIV patients, mild relative clinical impacts may become relevant due to substantial absolute FIV reductions. Admission CTP may help sorting patients according to expected drug effect profile.

There has been a comprehensive failure when attempting to translate promising therapies from the experimental setting to the clinical stage in severe traumatic brain injury (TBI). The reasons are multifactorial, but include an incomplete understanding of human TBI biology and inadequate optimization of drug design and dosage. The heterogeneity of the injury pattern, clinical severity, and variations in treatment as well as a changing epidemiology are additional challenges in TBI research. Evidently, the concept of “one size fits all” does not apply to TBI. While refined animal models of TBI have been crucial for understanding the injury mechanisms in TBI and in the screening for novel pharmacological treatments, information gained from these studies has not been translated into clinically relevant treatments. A stronger focus on large animal TBI models in preclinical research should be considered. For successful neuroprotective drug development, a “bench to bedside and back” strategy is suggested which may include proof of mechanisms, pharmacokinetic validation, and proof of concept studies in small, carefully selected cohorts of patients. Such experimental medicine design would use refined clinical research tools, including neuroimaging, tissue diagnosis, biomarkers, and neuromonitoring.

Resveratrol (3,5,4′-trihydroxy-trans-stilbene, Res), as a natural product and neuroprotective drug, plays important roles in the treatment of Parkinson’s disease (PD). However, Res is seriously hin...

Traumatic brain injury (TBI) is a major cause of mortality and long-term disability around the world. Even mild to moderate TBI can lead to lifelong neurological impairment due to acute and progressive neurodegeneration and neuroinflammation induced by the injury. Thus, the discovery of novel treatments which can be used as early therapeutic interventions following TBI is essential to restrict neuronal cell death and neuroinflammation. In this study, we demonstrate that orally administered treatment with N-acetyl-L-leucine (NALL) led to attenuation of cell death and reduced the expression of neuroinflammatory markers after controlled cortical impact (CCI) induced experimental TBI in mice. Our data indicate that partial restoration of autophagy flux mediated by NALL may account for the positive effect of treatment in the injured mouse brain. Taken together, our study indicates treatment with NALL would be expected to be beneficial in restricting neuronal death and hence improving neurological function after injury, and is a promising novel, neuroprotective drug candidate for the treatment of TBI.

Introduction: Tissue plasminogen activator (Alteplase; tPA) is the most commonly used thrombolytic medication for treatment of acute ischemic stroke, and recent research suggests that Tenecteplase (TNKase) is also effective. NA-1 is a novel neuroprotective drug intended to reduce disability when administered after stroke that is currently being studied in two late stage clinical trials, FRONTIER (NCT02315443) and ESCAPE-NA1 (NCT02930018). Given the overlap in the patient populations and the likelihood that subjects receiving NA-1 could receive thrombolysis, studies were performed to evaluate the effects of NA-1 on the fibrinolytic activity of tPA and TNKase. Methods: A spectrophotometric method of measuring clot formation and lysis in citrated human plasma was developed and used to assess the fibrinolytic activity of tPA and of TNKase. Aprotinin, a known protease inhibitor capable of blocking tPA and TNKase activity, was used as a positive control to demonstrate that the assay system was appropriately sensitive to detect inhibition of thrombolytic activity. Varying concentrations of NA-1 were added to the reaction to assess whether NA-1 could affect the rate of clot formation or the rate of clot lysis in the presence of tPA or TNKase. Results: The sensitivity of this assay system was demonstrated to enable detection of small changes in the fibrinolytic activity of tPA and TNKase on human plasma in the presence of thrombin. NA-1 did not display any fibrinolytic activity on its own nor did it affect the rate of clot formation in the system. NA-1 also did not affect the rate of clot formation or of fibrinolysis in the presence of tPA or TNKase. Conclusions: NA-1 has no intrinsic fibrinolytic activity and does not modulate the fibrinolytic activity of tPA or TNKase. Therefore, NA-1 can be given safely to stroke victims receiving tPA or TNKase without negatively impacting the potential benefit of thrombolysis. This method could also be used to assess other drugs that may have the potential to interact with or be concurrently administered to patients receiving thrombolytic medications.

Mildronate is a cardiac and neuroprotective drug that is widely used in some countries. By inhibiting carnitine biosynthesis, mildronate impairs the fatty acids transport into mitochondria, thereby decreasing the β-oxidation intensity. Since 2016, it has been prohibited by the World Anti-Doping Agency (WADA). However, the information on its safety and its influence on the athletes' health is scarce. There are no published studies on whether mildronate-induced long-term metabolism "rearrangement" may cause negative effects on high-metabolic-rate organs and on the whole organism. Here, we demonstrate that long-term mildronate treatment of healthy mice induced global metabolism change at the transcriptome level in liver, heart, and brain. Mildronate treatment also induced some behavioral changes such as anxiety-related behavior and diminished explorative behavior. We also found that mildronate induced a dysbiosis, as manifested by an increase in Proteobacteria level in gut microbiome. At the same time, the absence of a statistically significant increase in mouse strength and endurance procedures suggests that mildronate effect on productivity is negligible. The sum of our data suggests that long-term treatment of healthy mice with mildronate induces dysbiosis and behavioral deviations despite the effectiveness of mildronate for cardiac and neurological diseases. Thus, we suggest that long-term mildronate treatment is undesirable or at the very least should be accompanied by prebiotics treatments, but this issue should be studied further.

Parkinson disease (PD) is the most common neurodegenerative movement disorder. Currently only symptomatic treatments exist for PD, and so the search for potential neuroprotective drug targets is of great importance. Chaperone mediated autophagy (CMA) is one of the key cellular mechanisms in protein homeostasis. Many of the pathogenic pathways thought to be important in PD converge on CMA, thus rendering it an attractive therapeutic target. Areas covered: In this review we discuss current up-to-date knowledge of the molecular mechanisms involved in CMA function and regulation. We go on to discuss the links between CMA and PD including CMA's role in ɑ-synuclein processing, oxidative stress, and mitochondrial function. We finish by exploring the potential benefits of how upregulation of CMA may be beneficial in PD and strategies to achieve this. Expert opinion: Upregulation of CMA is an attractive therapeutic target in PD due to its links with several pathogenic pathways . Currently more knowledge of the mechanisms that regulate CMA is required to allow for the development of specific CMA modulators. However, recent studies demonstrating the role of retinoic acid derivatives and miRNAs in regulating CMA are promising, and indirect upregulation of CMA by modulating other lysosomal pathways may be helpful.

Here we used a systems biology approach and artificial intelligence to identify a neuroprotective agent for the treatment of peripheral nerve root avulsion. Based on accumulated knowledge of the neurodegenerative and neuroprotective processes that occur in motoneurons after root avulsion, we built up protein networks and converted them into mathematical models. Unbiased proteomic data from our preclinical models were used for machine learning algorithms and for restrictions to be imposed on mathematical solutions. Solutions allowed us to identify combinations of repurposed drugs as potential neuroprotective agents and we validated them in our preclinical models. The best one, NeuroHeal, neuroprotected motoneurons, exerted anti-inflammatory properties and promoted functional locomotor recovery. NeuroHeal endorsed the activation of Sirtuin 1, which was essential for its neuroprotective effect. These results support the value of network-centric approaches for drug discovery and demonstrate the efficacy of NeuroHeal as adjuvant treatment with surgical repair for nervous system trauma., This work was mainly supported by a grant from Fundació La Marató-TV3 (#110432, CC, AB & VP) that funded the work and contracts of TLR and MHG and partially by the Ministerio de Economía y Competitividad of Spain (#SAF 2014-59701, CC, DRG, & TLR). We are also grateful for support from CIBERNED and funding from the European Union Seventh Framework Programme for research, technological development, and demonstration (#306240, XN, FRP & CC). Part of the research leading to these results has also received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 306240.

A series of dimeric dipeptide mimetics of nerve growth factor (NGF) was obtained. One of these, bis-(N-monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamine (GK-2), designed on the basis of loop 4 beta-turn structure, was selected for development of a new potential neuroprotective drug. The paper describes the first stage of the GK-2 synthesis technology development – selection of the optimum synthetic scheme. Two nine-step schemes of synthesis, consisting in extension of the peptide chain from N- or C-terminal were considered. Condensation in both cases was carried out using N-hydroxysuccinimide esters. In the first case, Z (Bzl) groups were used for the protection of side functions. For the C-terminal carboxyl protection, salification was used. In the second scheme, Z/Boc strategy of protecting groups was used. For the first scheme, hexamethylenediamine was attached at the final stage, and in the second scheme – at the first stage. Both schemes have resulted in a product with the same optical and diastereomeric purity, did not require complex purification methods, and took approximately equal times. The method with peptide chain building from C-terminal proved to ensure 1.2 times lower cost of basic reagents per kilogram product and was selected as the basis for the development of laboratory regulations.

Screening brain-penetrable antioxidants from natural products is a promising way for neuroprotective drug discovery. However, there is no screening methodology enables simultaneous investigation of antioxidant activity and blood-brain barrier (BBB) permeability of compounds from complex samples. Here we propose a novel strategy by combining BBB specific parallel artificial membrane permeability assay with 1,1-diphenyl-2-picrylhydrazyl recognition (BBB-PAMPA-DPPH) to achieve rapid multicomponent screening. First, BBB specific artificial membrane was constructed to separate the compounds with high BBB permeability in herbal extracts. The antioxidant activity of the isolated compounds could be optically recognized through the bleaching of the purple-colored DPPH. By off-line combined HPLC-UV/Q-TOF-MS analysis, the exact BBB-penetrable compounds responsible for the antioxidant activity could be rapidly screened. With this approach, compound 2,6,4'-trihydroxy-4-methoxybenzophenon in Rhizoma Anemarrhena was found to be an antioxidant with very high BBB permeability, which could also be detected in rat plasma and brain tissue after oral administration. Our findings suggested the BBB-PAMPA-DPPH method could be a powerful tool for neuroprotective drug discovery from natural products.

Background: Presently, tissue plasminogen activator (tPA) is the sole FDA-approved antithrombotic treatment available for stroke. However, tPA’s harmful side effects within the central nervous system can exacerbate blood-brain barrier (BBB) damage and increase mortality. Patients should receive tPA less than 4.5 hours post-stroke. Although age alone is not an impediment for tPA treatment, the harmful effects of delayed tPA (>4.5h), particularly on aged stroke animals, have not been well studied. We reported that intracranial transplantation of neural stem cells (hNSCs) ameliorates BBB damage caused by ischemic stroke. In this study, we examined the combined effects of minocycline (a neuroprotective and anti-inflammatory drug) and hNSC transplantation on the mortality of delayed tPA-treated aged mice within 48h post-stroke. Methods and Results: We utilized the middle cerebral artery occlusion stroke mouse model to induce focal cerebral ischemia followed by reperfusion (MCAO/R). 6h post-MCAO, we administered tPA intravenously. Minocycline was administered intraperitoneally at various time points prior to tPA injection. One day post-stroke, we injected hNSCs intracranially. Previously, we reported that hNSCs (both human and mouse) transplanted into the brain 24h post-stroke rapidly improve neurological outcome in young-adult mice (4-5mo). In our current study, tPA administered within 4.5h did not increase mortality in either young-adult or aged mice. However, we found delayed tPA treatment (6h post-stroke) significantly increased the mortality of aged mice (13-18 mo) but not in young-adult mice. Here, we report that by combining minocycline prior to tPA significantly reduced mortality. Furthermore, transplanting hNSCs in minocycline-treated mice further ameliorated the pathophysiology caused by delayed tPA. Conclusions: Our findings implicate that administering the anti-apototic and anti-inflammatory drug prior to tPA injection, and then post-treating with multipotent neuroprotective hNSCs might expand the time window of tPA and reduce reperfusion injury.

Despite the availability of promising stroke therapeutics in rodents, none other than thrombolytics have shown a conclusive clinical benefit in human trials. Stroke research in primates may be a plausible means to bridge research conducted in lower-order species with that conducted in humans, especially in the field of neuroprotection. This suggestion is made by the Stroke Therapy Academic Industry Roundtable (STAIR) committee, proposing that promising therapies should be tested in nonhuman primates (NHPs) before advancing to clinical trials. However, due to the paucity of stroke studies in NHPs, few experimental models have been described. Critical factors in designing NHP stroke models include the choice of species, the method of inducing the stroke and the choice of outcome measures. In this review, we describe established NHP models of stroke and discuss factors that may influence model development. We focus on models that may be useful for neuroprotective drug screening before clinical trials.

Stroke is usually treated by systemic thrombolytic therapy if the patient presents within an appropriate time window. There is also widespread interest in the development of thrombolytic agents that can be used in cases of delayed presentation. Current agents that can be used in cases of delayed presentation of nerve damage by thrombus. Current systemic thrombolytic therapy is associated with adverse effects such as fibrinogenolysis and bleeding. In an attempt to increase the efficacy, safety, and specificity of thrombolytic therapy, a number of targeted thrombolytic agents have been studied in recent years. This review focuses on the concepts underlying targeted thrombolytic therapy and describes recent drug developments in this field.

Back ground: Arthrospira platensis encompasses vital nutrients and is commercialized globally. It comprises of imperative resource that has the potential to combat neurological deformities caused due to stress and anxiety. Objective: This work evaluates the neuroprotective effect of spirulina cultivated on nitrogen enriched medium and compares it with the commercial samples. Materials and Methods: The study is authenticated with an antioxidant assay and the vital compounds are relatively profiled by GC-MS study. Furthermore, a molecular docking analysis is implemented to investigate the therapeutic potentials of the phytocompounds against Monoamine Oxidase –A and establish them as inhibitors. The ethanolic extract of spirullina as are fed on depressed mice models to assay its neuroprotective effect and rehabilitation of brain cells by a histopathological study. Results: The antioxidant content of the augmented sample was consistent on par with the commercial sample. The in silico assay was performed with 10 extricated compounds of both the samples where, Butanoic acid, 3-hydroxy- furnished a minimum binding affinity energy value of -56.24 kcal/mol and dodecanamide was efficient to bind with the active site of the amino acid residue TYR 69 with a minimum energy of -87.8 kcal/mol. The histopathological examination upholds the refurbished parameter of vital phytocompounds with placid cellular edema and perivascular infiltration. Conclusion: There is a wide range of need to develop research against stress and anxiety and the study fortifies the restorative efficacy of the phytocompounds as a neuroprotective drug.

This manuscript describes the synthesis of a new series of 2-amino-6-(trifluoromethoxy)benzoxazole derivatives (1–5) and a benzothiazine derivative (6) structurally related to riluzole, the only neuroprotective drug currently approved for the treatment of the amyotrophic lateral sclerosis. Preliminary results indicate that the synthesized compounds, in particular benzamide derivatives 3 and 4, are able to antagonize voltage-dependent Na+ channel currents, and therefore they could be exploited as new inhibitors of these channels. Moreover, all compounds possess low binding affinity for GABA and NMDA receptors.

We studied the effects of new nootropic and neuroprotective drug Noopept (N-phenylacetyl-L-prolylglycine ethyl ester) in various dosage regimens on the dynamics of glycemia, body weight, and pain sensitivity in rats receiving diabetogenic toxin streptozotocin. In experimental diabetic rats, Noopept alleviated glycemia and weight loss and normalized enhanced pain sensitivity. The normalizing effect of Noopept was most pronounced when it was administered as a preventive agent prior to injection of the toxin. Both preventive and therapeutic administration of Noopept (delayed injections included) significantly weakened the examined metabolic effects of diabetogenic toxin. Possible mechanisms of the antidiabetic action of Noopept are analyzed.

Traumatic brain injuries (TBI) are increasing cause of functional disability which requires aggressive researches on neuroprotective agents to prevent or rectify the consequences of organic brain damage and to enhance rehabilitation. Many of the drugs which proves beneficial in preclinical studies failed to translate into clinical practice, hence the search for the ideal neuroprotective drug continues. Since the pathophysiology of TBI is highly complex and variable with multiple factors playing their roles simultaneously, it's a very tiring job to find out a novel agent. When we try to alter one of the patho-physiological aspect of TBI, it affects many targets at a time, in the same manner as the waves affect the multiple points when we throw an object into pond. As the many aspects of the TBI are still obscured, it will be of great difficulty to search a suitable target which has got pronounced effect on TBI. The failure of newer molecules to fulfill its promise can also be attributed to the flaw in pre- clinical and clinical studies. Eventually the journey to have an ideal neuroprotective agent still continues.

Acute ischemic stroke is inadequately treated in the USA and worldwide due to a lengthy history of neuroprotective drug failures in clinical trials. The majority of victims must endure life-long disabilities that not only affect their livelihood, but also have an enormous societal economic impact. The rapid development of a neuroprotective or cytoprotective compound would allow future stroke victims to receive a treatment to reduce disabilities and further promote recovery of function. This opinion article reviews in detail the enormous costs associated with developing a small molecule to treat stroke, as well as providing a timely overview of the cell-death time-course and relationship to the ischemic cascade. Distinct temporal patterns of cell-death of neurovascular unit components provide opportunities to intervene and optimize new cytoprotective strategies. However, adequate research funding is mandatory to allow stroke researchers to develop and test their novel therapeutic approach to treat stroke victims.

The North American Clinical Trials Network (NACTN) for the Treatment of Spinal Cord Injury is a consortium of 10 neurosurgery departments, a data management center, and a pharmacological center. The NACTN was established with the goal of bringing recent molecular and cell-based discoveries in neuroprotection and regeneration from the laboratory into clinical trials that optimize meaningful data outcomes and maximum safety to patients. The requirements of planning and executing clinical trials in spinal cord injury (SCI) and the steps that the NACTN has taken to address these requirements are discussed and illustrated in articles in this issue of the Journal of Neurosurgery: Spine. The progress that the NACTN has made in meeting these goals can be summarized as organizing a network of hospitals capable of enrolling a sufficient number of patients for conducting Phase I and II trials; creating a Data Management Center and a database of the natural history of recovery after SCI (at the time of this writing 485 patients were enrolled in the database); creating a database of the incidence and severity of complications that occur during acute and subacute treatment after SCI; developing a Pharmacological Center capable of performing pharmacokinetic and pharmacodynamic studies of therapeutic drugs; completing enrollment of 36 patients in NACTN's first clinical trial, a Phase I study of riluzole, a neuroprotective drug; and performing pharmacokinetic and pharmacodynamic studies of riluzole in acute SCI.

Recombinant erythropoietin (rEPO) failed in a recent clinical study to protect from damages induced by ischemic stroke. The lack of acute treatments in ischemic stroke and the promising outcome in numerous preclinical studies in vivo demands a more critical evaluation of the future use of EPO as an acute treatment.The current use and administration of rhEPO and its analogs in animal models and the future use of this cytokine in the treatment of ischemic stroke.In this review the potential reasons for the failure of EPO in the clinical trial are analysed and whether the preclinical trials sufficiently evaluated the true potential of recombinant EPO and its analogs is assessed. Alternative methods for administration of EPO to enhance its potential as a neuroprotective drug in ischemic stroke are discussed.Failure in clinical trial does not necessarily indicate the lack of therapeutic potential of EPO. This review encourages further investigation of the true potential of EPO as a candidate drug for the treatment of ischemic stroke by improved preclinical experimental design and utilization of alternative administration methods.

Traumatic brain injury (TBI) is one of the most frequent causes of combat casualties in Operations Iraqi Freedom (OIF), Enduring Freedom (OEF), and New Dawn (OND). Although less common than combat-related blast exposure, there have been significant numbers of blast injuries in civilian populations in the United States. Current United States Department of Defense (DoD) ICD-9 derived diagnoses of TBI in the DoD Health Care System show that, for 2016, severe and moderate TBIs accounted for just 0.7% and 12.9%, respectively, of the total of 13,634 brain injuries, while mild TBIs (mTBIs) accounted for 86% of the total. Although there is a report that there are differences in the frequency of long-term complications in mTBI between blast and non-blast TBIs, clinical presentation is classified by severity score rather than mechanism because severity scoring is associated with prognosis in clinical practice. Blast TBI (bTBI) is unique in its pathology and mechanism, but there is no treatment specific for bTBIs—these patients are treated similarly to TBIs in general and therapy is tailored on an individual basis. Currently there is no neuroprotective drug recommended by the clinical guidelines based on evidence.

The amino derivatives of diamantane and triamantane, representing close topological analogues of the neuroprotective drug Memantine®, were prepared via amination of the respective carboxylic acids or alcohols.

More accurate documentation of a neonate's specific hypertonic state could be helpful as part of serial neurologic examinations. The clinician would then be in a more advantageous position to choose the appropriate neuroprotective drug or the procedure that best fits with the etiology, localization, and timing of injury. Ideally, choices for neuroprotection will integrate history, examination, and diagnostic findings before considering options for prophylaxis, neurorescue, or neurorepair. Measuring the efficacy of a neuroprotection protocol should include a complete list of life-course challenges, including motor, epileptic, cognitive, and behavioral outcomes as expressed at successively older ages.

Neurodegenerative disorders are caused by the death and dysfunction of brain cells, but despite a huge worldwide effort, no neuroprotective treatments that slow cell death currently exist. The failure of translation from animal models to humans in the clinic is due to many factors including species differences, human brain complexity, age, patient variability and disease-specific phenotypes. Additional methods are therefore required to overcome these obstacles in neuroprotective drug development. Incorporating target validation using human brain-tissue microarray screening and direct human brain-cell testing at an early preclinical stage to isolate molecules that protect the human brain may be an effective strategy.