Search

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Following the realization that cerebral tissue may survive for hours after an ischaemic insult, several agents with neuroprotective properties in small-animal models of cerebral ischaemia have been tested in patients with acute ischaemic stroke (AIS). Initial attempts at translating the positive effects of these agents from animal models to patients were unsuccessful, possibly as a result of poorly planned experiments in models of ischaemia, and/or clinical trials of AIS that were not optimized to show a positive effect. Newer neuroprotective agents that are believed to act later in the ischaemic cascade may offer a greater chance of success. However, before these agents can be introduced into clinical practice they must undergo assessment in rodent and large-animal models of AIS and, in particular, the dose-response relationship and the treatment time window should be defined. This should be followed by evaluation in carefully designed clinical trials of adequate power, involving subjects receiving an appropriate dose within an optimum time window following the onset of symptoms. There is hope that such careful strategies may guide continued progress in neuroprotective drug development.

Abstract —The plethora of failed clinical trials with neuroprotective drugs for acute ischemic stroke have raised justifiable concerns about how best to proceed for the future development of such interventions. Preclinical testing of neuroprotective drugs is an important aspect of assessing their therapeutic potential, but guidelines concerning how to perform preclinical development of purported neuroprotective drugs for acute ischemic stroke are lacking. This conference of academicians and industry representatives was convened to suggest such guidelines for the preclinical evaluation of neuroprotective drugs and to recommend to potential clinical investigators the data they should review to reassure themselves that a particular neuroprotective drug has a reasonable chance to succeed in an appropriately designed clinical trial. Without rigorous, robust, and detailed preclinical evaluation, it is unlikely that novel neuroprotective drugs will prove to be effective when tested in large, time-consuming, and expensive clinical trials. Additionally, similar recommendations are provided for drugs with the potential to enhance recovery after acute ischemic stroke, a burgeoning new field with great potential but little currently available data. The suggestions contained in this document are meant to serve as overall guidelines that must be adapted to the individual characteristics related to particular drugs and their preclinical and clinical development needs.

Background Therapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future treatment of multiple sclerosis (MS), as well as other diseases. Laquinimod (LQ) is an orally administered, central nervous system (CNS)-active immunomodulator with demonstrated efficacy in MS clinical trials and a favorable safety and tolerability profile. Aims We aimed to explore the pathological, functional, and behavioral consequences of prophylactic and therapeutic (after presentation of peak clinical disease) LQ treatment in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Materials and methods Active EAE-induced 8-week-old C57BL/6 mice were treated with 5 or 25 mg/kg/day LQ via oral gavage beginning on EAE post-immunization day 0, 8, or 21. Clinical scores and rotorod motor performance were assessed throughout the disease course. Immune analysis of autoantigen-stimulated splenocytes, electrophysiological conduction of callosal axons, and immunohistochemistry of white matter-rich corpus callosum and spinal cord were performed. Results Prophylactic and therapeutic treatment with LQ significantly decreased mean clinical disease scores, inhibited Th1 cytokine production, and decreased the CNS inflammatory response. LQ-induced improvement in axon myelination and integrity during EAE was functional, as evidenced by significant recovery of callosal axon conduction and axon refractoriness and pronounced improvement in rotorod motor performance. These improvements correlate with LQ-induced attenuation of EAE-induced demyelination and axon damage, and improved myelinated axon numbers. Discussion Even when initiated at peak disease, LQ treatment has beneficial effects within the chronic EAE mouse model. In addition to its immunomodulatory effects, the positive effects of LQ treatment on oligodendrocyte numbers and myelin density are indicative of significant, functional neuroprotective and neurorestorative effects. Conclusions Our results support a potential neuroprotective, in addition to immunomodulatory, effect of LQ treatment in inhibiting ongoing MS/EAE disease progression.

The identification of a drug that stimulates endogenous myelination and spares axon degeneration during multiple sclerosis (MS) could potentially reduce the rate of disease progression. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we have previously shown that prophylactic administration of the estrogen receptor (ER) β ligand 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) decreases clinical disease, is neuroprotective, stimulates endogenous myelination, and improves axon conduction without altering peripheral cytokine production or reducing central nervous system (CNS) inflammation. Here, we assessed the effects of therapeutic DPN treatment during peak EAE disease, which represents a more clinically relevant treatment paradigm. In addition, we investigated the mechanism of action of DPN treatment-induced recovery during EAE. Given that prophylactic and therapeutic treatment with DPN during EAE improved remyelination-induced axon conduction, and that ER (α and β) and membrane (m)ERs are present on oligodendrocyte lineage cells, a direct effect of treatment on oligodendrocytes is likely. DPN treatment of EAE animals resulted in phosphorylated ERβ and activated the phosphatidylinositol 3-kinase (PI3K)/ serine–threonine-specific protein kinase (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway, a pathway required for oligodendrocyte survival and axon myelination. These results, along with our previous studies of prophylactic DPN treatment, make DPN and similar ERβ ligands immediate and favorable therapeutic candidates for demyelinating disease.

Paradigm shift in neuroprotective drug development: clinically tolerated NMDA receptor inhibition by memantine

All prior drug development programs of neuroprotective agents were unsuccessful for a variety of reasons related to both preclinical assessment and the design/implementation of clinical trials. The neuroprotection hypothesis of improving functional outcome related to salvaging ischemic brain tissue is strongly supported by robust preclinical data for many agents. In the future, monotherapy neuroprotection trials will be difficult but could be performed in underused centers with drugs that have very promising and complete preclinical results. Additional approaches for the testing and use of neuroprotective agents should be considered. Novel approaches would include extending penumbral survival for the later use of reperfusion therapy, reducing reperfusion injury after successful reperfusion, and using drugs with both neuroprotective and recovery enhancing effects, as exemplified by granulocyte colony–stimulating factor and citicoline. To maximize outcome after stroke, the combined use or reperfusion and neuroprotection is likely to be needed, so we must begin to perform carefully designed trials with this combination.

Many drugs that have been developed to treat neurodegenerative diseases fail to gain approval for clinical use because they are not well tolerated in humans. In this article, I describe a series of strategies for the development of neuroprotective therapeutics that are both effective and well tolerated. These strategies are based on the principle that drugs should be activated by the pathological state that they are intended to inhibit. This approach has already met with success, and has led to the development of the potentially neuroprotective drug memantine, an N-methyl-D-aspartate (NMDA)-type and glutamate receptor antagonist.

Background — Neuroprotective drugs for acute stroke have appeared to work in animals, only to fail when tested in humans. With the failure of so many clinical trials, the future of neuroprotective drug development is in jeopardy. Current hypotheses and methodologies must continue to be reevaluated, and new strategies need to be explored. Summary of Review — In part 1, we review key challenges and complexities in translational stroke research by focusing on the “disconnect” in the way that neuroprotective agents have traditionally been assessed in clinical trials compared with animal models. In preclinical studies, determination of neuroprotection has relied heavily on assessment of infarct volume measurements (instead of functional outcomes), short-term (instead of long-term) end points, transient (instead of permanent) ischemia models, short (instead of extended) time windows for drug administration, and protection of cerebral gray matter (instead of both gray and white matter). Clinical trials have often been limited by inappropriately long time windows, insufficient statistical power, insensitive outcome measures, inclusion of protocol violators, failure to target specific stroke subtypes, and failure to target the ischemic penumbra. In part 2, we explore new concepts in ischemic pathophysiology that should encourage us also to think beyond the hyperacute phase of ischemia and consider the design of trials that use multiagent therapy and exploit the capacity of the brain for neuroplasticity and repair. Conclusions — By recognizing the strengths and limitations of animal models of stroke and the shortcomings of previous clinical trials, we hope to move translational research forward for the development of new therapies for the acute and subacute stages after stroke.

Glaucoma is an optic neuropathy characterized by progressive loss of retinal ganglion cells (RGCs). Death of ganglion cells is not always only pressure dependent mechanism but also have several pressure independent mechanism that establish a cascade of changes that ultimately leads to cell death. Neuro- protection is a process that attempt to preserve the cells that were spared during initial insult, but are still vulnerable to damage. Although not yet available, a neuroprotective agent would be great use that rescue neurons already compromised or that promote regrowth of axonal or dendritic connection to restore function. This review based on literature, giving the idea of varies mechanism of RGC death delineated by research and discussed some pharmacological agent believed to have a neuroprotective role in glaucoma. DOI: 10.3329/bjms.v9i4.6685Bangladesh Journal of Medical Science Vol.09 No.4 July 2010 pp.199-203

Treatment of neurodegenerative diseases has become one of the most challenging topics of the last decades due to their prevalence and increasing societal cost. The crucial point of the non-invasive therapeutic strategy for neurological disorder treatment relies on the drugs’ passage through the blood-brain barrier (BBB). Indeed, this biological barrier is involved in cerebral vascular homeostasis by its tight junctions, for example. One way to overcome this limit and deliver neuroprotective substances in the brain relies on nanotechnology-based approaches. Poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) are biocompatible, non-toxic, and provide many benefits, including improved drug solubility, protection against enzymatic digestion, increased targeting efficiency, and enhanced cellular internalization. This review will present an overview of the latest findings and advances in the PLGA NP-based approach for neuroprotective drug delivery in the case of neurodegenerative disease treatment (i.e., Alzheimer’s, Parkinson’s, Huntington’s diseases, Amyotrophic Lateral, and Multiple Sclerosis).