Effective Neuroprotective Drugs Research Articles

Ganoderic acid a decreased Aβ42-induced neurotoxicity in PC12 cells by reduced mitochondrial damage

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Accumulation of β-amyloid (Aβ) in the brain has been recognized as a key factor in the onset and progression of Alzheimer’s disease (AD).The accumulation of Aβ in the brain catalyzes the production of reactive oxygen species (ROS), which in turn triggers oxidative damage to cellular components such as DNA, lipids, and proteins. In the present study, we investigated the protective effect of Ganoderic acid A (GA.A) against Aβ42-induced apoptosis in PC12 cells. Changes in mitochondrial membrane potential indicated that GA.A treats mitochondrial dysfunction by decreasing Aβ42 deposition and inhibiting neural protofiber tangle formation. Changes in intracellular Ca2+ and caspase-3 indicated that GA.A reduced mitochondrial damage by Aβ42 in PC12 cells, thereby decreasing ROS accumulation and reducing Aβ protofiber-induced cytotoxicity. These features suggest that GA.A has great potential as an effective neuroprotective drug in the treatment of Alzheimer’s disease.

Angiostrongylus cantonensis induces energy imbalance and dyskinesia in mice by reducing the expression of melanin-concentrating hormone

BackgroundInfection with Angiostrongylus cantonensis (AC) in humans or mice can lead to severe eosinophilic meningitis or encephalitis, resulting in various neurological impairments. Developing effective neuroprotective drugs to improve the quality of life in affected individuals is critical.MethodsWe conducted a Gene Ontology enrichment analysis on microarray gene expression (GSE159486) in the brains of AC-infected mice. The expression levels of melanin-concentrating hormone (MCH) were confirmed through real-time quantitative PCR (RT–qPCR) and immunofluorescence. Metabolic parameters were assessed using indirect calorimetry, and mice’s energy metabolism was evaluated via pathological hematoxylin and eosin (H&E) staining, serum biochemical assays, and immunohistochemistry. Behavioral tests assessed cognitive and motor functions. Western blotting was used to measure the expression of synapse-related proteins. Mice were supplemented with MCH via nasal administration.ResultsPostinfection, a marked decrease in Pmch expression and the encoded MCH was observed. Infected mice exhibited significant weight loss, extensive consumption of sugar and white fat tissue, reduced movement distance, and decreased speed, compared with the control group. Notably, nasal administration of MCH countered the energy imbalance and dyskinesia caused by AC infection, enhancing survival rates. MCH treatment also increased the expression level of postsynaptic density protein 95 (PSD95) and microtubule-associated protein-2 (MAP2), as well as upregulated transcription level of B cell leukemia/lymphoma 2 (Bcl2) in the cortex.ConclusionsOur findings suggest that MCH improves dyskinesia by reducing loss of synaptic proteins, indicating its potential as a therapeutic agent for AC infection.Graphical

391 Intraarterial Verapamil for Neuroprotection in Ischemic Stroke

INTRODUCTION: Verapamil is an FDA-approved calcium channel blocker administered for the standard-of-care treatment of vasospasm. Preclinical studies have shown that verapamil reduces inflammation and protects penumbra neurons from further damage and eventual death. METHODS: Patients were recruited based on inclusion and exclusion criteria in a clinical protocol reviewed and approved by two institutional review boards. The final cohort comprised 42 emergency care patients with an acute onset focal neurological deficit consistent with ischemic stroke and/or a computed tomographic scan consistent with acute cerebral ischemia. All patients were 18 years of age or older that presented within 24 hours of symptom onset and had a significant but not severe neurological deficit, measured by a National Institutes of Health Stroke Scale (NIHSS) score greater than four but less than 22. All patients received a mechanical thrombectomy intervention after identifying a large vessel occlusion (LVO). RESULTS: The Verapamil-treated group (N = 23) included 22 patients with middle cerebral artery (MCA) occlusions and 1 with a basilar posterior cerebral artery (PCA) occlusion. In these patients, investigators administered 10 mg of Verapamil intraarterially following mechanical thrombectomy. Patients exposed to control conditions (N = 19) were matched for age, biological sex, admission NIHSS score, occlusion location, administration of tPA, and achieved TICI score. Intraarterial Verapamil treatment did not significantly increase sICH, hemorrhagic transformation, or death compared to standard of care treatment, demonstrating safety in an acute ischemic stroke patient population. Verapamil treatment was associated with significantly greater changes in mRS score, improved recovery time, and shortened length of hospital stay compared to standard-of-care treatment. CONCLUSIONS: This study suggests that verapamil is a safe and effective neuroprotective drug in ischemic stroke clinical populations that require mechanical thrombectomy for treatment.

TAT-W61 peptide attenuates neuronal injury through blocking the binding of S100b to the V-domain of Rage during ischemic stroke.

Ischemic stroke is a devastative nervous system disease associated with high mortality and morbidity rates. Unfortunately, no clinically effective neuroprotective drugs are available now. In ischemic stroke, S100 calcium-binding protein b (S100b) binds to receptor for advanced glycation end products (Rage), leading to the neurological injury. Therefore, disruption of the interaction between S100B and Rage can rescue neuronal cells. Here, we designed a peptide, termed TAT-W61, derived from the V domain of Rage which can recognize S100b. Intriguingly, TAT-W61 can reduce the inflammatory caused by ischemic stroke through the direct binding to S100b. The further investigation demonstrated that TAT-W61 can improve pathological infarct volume and reduce the apoptotic rate. Particularly, TAT-W61 significantly improved the learning ability, memory, and motor dysfunction of the mouse in the ischemic stroke model. Our study provides a mechanistic insight into the abnormal expression of S100b and Rage in ischemic stroke and yields an invaluable candidate for the development of drugs in tackling ischemic stroke. KEY MESSAGES: S100b expression is higher in ischemic stroke, in association with a high expression of many genes, especially of Rage. S100b is directly bound to the V-domain of Rage. Blocking the binding of S100b to Rage improves the injury after ischemic stroke.

Recent Advances and Therapeutic Implications of 2-Oxoglutarate-Dependent Dioxygenases in Ischemic Stroke.

Ischemic stroke is a common disease with a high disability rate and mortality, which brings heavy pressure on families and medical insurance. Nowadays, the golden treatments for ischemic stroke in the acute phase mainly include endovascular therapy and intravenous thrombolysis. Some drugs are used to alleviate brain injury in patients with ischemic stroke, such as edaravone and 3-n-butylphthalide. However, no effective neuroprotective drug for ischemic stroke has been acknowledged. 2-Oxoglutarate-dependent dioxygenases (2OGDDs) are conserved and common dioxygenases whose activities depend on O2, Fe2+, and 2OG. Most 2OGDDs are expressed in the brain and are essential for the development and functions of the brain. Therefore, 2OGDDs likely play essential roles in ischemic brain injury. In this review, we briefly elucidate the functions of most 2OGDDs, particularly the effects of regulations of 2OGDDs on various cells in different phases after ischemic stroke. It would also provide promising potential therapeutic targets and directions of drug development for protecting the brain against ischemic injury and improving outcomes of ischemic stroke.

The Role of Hydrogen Sulfide in the Localization and Expression of p53 and Cell Death in the Nervous Tissue in Traumatic Brain Injury and Axotomy.

Traumatic brain injury (TBI) is one of the leading causes of disability and death worldwide. It is characterized by various molecular-cellular events, with the main ones being apoptosis and damage to axons. To date, there are no clinically effective neuroprotective drugs. In this study, we examined the role of hydrogen sulfide (H2S) in the localization and expression of the key pro-apoptotic protein p53, as well as cell death in the nervous tissue in TBI and axotomy. We used a fast donor (sodium sulphide, Na2S) H2S and a classic inhibitor (aminooxyacetic acid, AOAA) of cystathionine β-synthase (CBS), which is a key enzyme in H2S synthesis. These studies were carried out on three models of neurotrauma in vertebrates and invertebrates. As a result, it was found that Na2S exhibits a pronounced neuroprotective effect that reduces the number of TUNEL-positive neurons and glial cells in TBI and apoptotic glia in axotomy. This effect could be realized through the Na2S-dependent decrease in the level of p53 in the cells of the nervous tissue of vertebrates and invertebrates, which we observed in our study. We also observed the opposite effect when using AOAA, which indicates the important role of CBS in the regulation of p53 expression and death of neurons and glial cells in TBI and axotomy.

MesenchymAl stromal cells for Traumatic bRain Injury (MATRIx): a study protocol for a multicenter, double-blind, randomised, placebo-controlled phase II trial

BackgroundTraumatic brain injury (TBI) is a significant cause of death and disability, with no effective neuroprotective drugs currently available for its treatment. Mesenchymal stromal cell (MSC)-based therapy shows promise as MSCs release various soluble factors that can enhance the injury microenvironment through processes, such as immunomodulation, neuroprotection, and brain repair. Preclinical studies across different TBI models and severities have demonstrated that MSCs can improve functional and structural outcomes. Moreover, clinical evidence supports the safety of third-party donor bank-stored MSCs in adult subjects. Building on this preclinical and clinical data, we present the protocol for an academic, investigator-initiated, multicenter, double-blind, randomised, placebo-controlled, adaptive phase II dose-finding study aiming to evaluate the safety and efficacy of intravenous administration of allogeneic bone marrow-derived MSCs to severe TBI patients within 48 h of injury.Methods/designThe study will be conducted in two steps. Step 1 will enrol 42 patients, randomised in a 1:1:1 ratio to receive 80 million MSCs, 160 million MSCs or a placebo to establish safety and identify the most promising dose. Step 2 will enrol an additional 36 patients, randomised in a 1:1 ratio to receive the selected dose of MSCs or placebo. The activity of MSCs will be assessed by quantifying the plasmatic levels of neurofilament light (NfL) at 14 days as a biomarker of neuronal damage. It could be a significant breakthrough if the study demonstrates the safety and efficacy of MSC-based therapy for severe TBI patients. The results of this trial could inform the design of a phase III clinical trial aimed at establishing the efficacy of the first neurorestorative therapy for TBI.DiscussionOverall, the MATRIx trial is a critical step towards developing an effective treatment for TBI, which could significantly improve the lives of millions worldwide affected by this debilitating condition.Trial Registration EudraCT: 2022-000680-49.

The Role of Hydrogen Sulfide in Regulation of Cell Death following Neurotrauma and Related Neurodegenerative and Psychiatric Diseases.

Injuries of the central (CNS) and peripheral nervous system (PNS) are a serious problem of the modern healthcare system. The situation is complicated by the lack of clinically effective neuroprotective drugs that can protect damaged neurons and glial cells from death. In addition, people who have undergone neurotrauma often develop mental disorders and neurodegenerative diseases that worsen the quality of life up to severe disability and death. Hydrogen sulfide (H2S) is a gaseous signaling molecule that performs various cellular functions in normal and pathological conditions. However, the role of H2S in neurotrauma and mental disorders remains unexplored and sometimes controversial. In this large-scale review study, we examined the various biological effects of H2S associated with survival and cell death in trauma to the brain, spinal cord, and PNS, and the signaling mechanisms underlying the pathogenesis of mental illnesses, such as cognitive impairment, encephalopathy, depression and anxiety disorders, epilepsy and chronic pain. We also studied the role of H2S in the pathogenesis of neurodegenerative diseases: Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, we reviewed the current state of the art study of H2S donors as neuroprotectors and the possibility of their therapeutic uses in medicine. Our study showed that H2S has great neuroprotective potential. H2S reduces oxidative stress, lipid peroxidation, and neuroinflammation; inhibits processes associated with apoptosis, autophagy, ferroptosis and pyroptosis; prevents the destruction of the blood-brain barrier; increases the expression of neurotrophic factors; and models the activity of Ca2+ channels in neurotrauma. In addition, H2S activates neuroprotective signaling pathways in psychiatric and neurodegenerative diseases. However, high levels of H2S can cause cytotoxic effects. Thus, the development of H2S-associated neuroprotectors seems to be especially relevant. However, so far, all H2S modulators are at the stage of preclinical trials. Nevertheless, many of them show a high neuroprotective effect in various animal models of neurotrauma and related disorders. Despite the fact that our review is very extensive and detailed, it is well structured right down to the conclusions, which will allow researchers to quickly find the proper information they are interested in.

Research Progress on Neuroprotective Effects of Isoquinoline Alkaloids.

Neuronal injury and apoptosis are important causes of the occurrence and development of many neurodegenerative diseases, such as cerebral ischemia, Alzheimer's disease, and Parkinson's disease. Although the detailed mechanism of some diseases is unknown, the loss of neurons in the brain is still the main pathological feature. By exerting the neuroprotective effects of drugs, it is of great significance to alleviate the symptoms and improve the prognosis of these diseases. Isoquinoline alkaloids are important active ingredients in many traditional Chinese medicines. These substances have a wide range of pharmacological effects and significant activity. Although some studies have suggested that isoquinoline alkaloids may have pharmacological activities for treating neurodegenerative diseases, there is currently a lack of a comprehensive summary regarding their mechanisms and characteristics in neuroprotection. This paper provides a comprehensive review of the active components found in isoquinoline alkaloids that have neuroprotective effects. It thoroughly explains the various mechanisms behind the neuroprotective effects of isoquinoline alkaloids and summarizes their common characteristics. This information can serve as a reference for further research on the neuroprotective effects of isoquinoline alkaloids.

Are GABAergic drugs beneficial in providing neuroprotection after traumatic brain injuries? A comprehensive literature review of preclinical studies.

Traumatic brain injuries (TBI) caused by physical impact to the brain can adversely impact the welfare and well-being of the affected individuals. One of the leading causes of mortality and dysfunction in the world, TBI is a major public health problem facing the human community. Drugs that target GABAergic neurotransmission are commonly used for sedation in clinical TBI yet their potential to cause neuroprotection is unclear. In this paper, I have performed a rigorous literature review of the neuroprotective effects of drugs that increase GABAergic currents based on the results reported in preclinical literature. The drugs covered in this review include the following: propofol, benzodiazepines, barbiturates, isoflurane, and other drugs that are agonists of GABAA receptors. A careful review of numerous preclinical studies reveals that these drugs fail to produce any neuroprotection after a primary impact to the brain. In numerous circumstances, they could be detrimental to neuroprotection by increasing the size of the contusional brain tissue and by severely interfering with behavioral and functional recovery. Therefore, anesthetic agents that work by enhancing the effect of neurotransmitter GABA should be administered with caution of TBI patients until a clear and concrete picture of their neuroprotective efficacy emerges in the clinical literature.

The 6-AF Evaluation of Neuroprotective Activity against Cd- Induced Oxidative Stress and Degenerative Brain Disease including PD in Mice

Background: The neurotoxicity caused by Cadmium (Cd) has been researched internationally. Since it has a wide range of unfavorable effects on people, it is believed to be one of the primary tissue-inducing target agents. Using adult male albino mice, the therapeutic potential of 6-AF to reduce memory impairment, neurodegeneration, and neuroinflammation caused by Cadmium Chloride (CdCl2) was evaluated in the current study for the first time.
 Methodology: The male adult mice were distributed into 4 sub-groups; Control, Cd treated (1 mg/kg thrice weeks), Cd (1 mg/kg 3 weeks) + 6-AF (30 mg/kg 3 a week for last 2 weeks) and 6-AF treated (30 mg/kg thrice a week for the last two weeks). After the initial seven-day Cdcl2 dosing cycle, the 6-Aminoflavone was administered interpretively intravenously for the following around 14 days (three per week). After receiving Cdcl2 injections for 30 days, behavior tests were conducted. Western blot analysis was performed after the hippocampus was extracted, and the results were then used to develop the X-rays.
 Results: Our results demonstrate that 6-AF significantly enhanced behavior as assessed by the Y-maze and Morris Water Maze (MWM) and that this enhancement was followed by an inhibition of phospho C-Jun N Terminal Kinase (p-JNK) and its downstream signaling, including tumor necrosis factor-alpha (TNF-alpha), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-KB), and Poly (ADP-ribose In addition, 6-AF also reduced the expression of NRF-2 proteins in adult mice exposed to oxidative stress caused by cadmium chloride.
 Conclusion: 6-AF is an effective neuroprotective drug in disorders causing neurodegeneration.

Comparative study of the specific activity of soft application drugs with vinpocetine

In modern neurology, the main component of successful treatment of cerebrovascular pathology is pharmacotherapy. At the same time, the arsenal of effective medicines of evidence-based medicine in this area is quite limited. Vinpocetine (Cavinton) is one of the drugs that effectively selectively corrects cerebral perfusion. The use of alternative ways of absorption of vinpocetine (rectal and nasal) in certain soft application dosage forms will allow to significantly increase the bioavailability of the medicinal substance, reduce the level of adverse reactions from its use and expand the pharmacotherapeutic arsenal of domestic effective neuroprotective drugs. Taking into account the above, the employees of the Department of Medicines Technology of Zaporizhzhia State Medical University, on the basis of complex physical-chemical, pharmacotechnological, rheological and biopharmaceutical research, proposed rational formulations and technologies of two new soft application dosage forms of vinpocetine – rectal suppositories on a lipophilic basis and nasal cream on an emulsion basis for the therapy of arterial hypertension of II–III stages with cerebrovascular complications, reduction of the manifestation of neurological and/or mental symptoms in various forms of cerebral blood circulation insufficiency, consequences of a stroke, transient ischemic attack, etc. The aim of the work is to study the specific activity of the proposed innovative application dosage forms of vinpocetine. Materials and methods. Nasal ointment containing 0.5 % vinpocetine on an emulsion basis and rectal suppositories with vinpocetine 0.01 g on a lipophilic carrier were used as the object of preclinical studies, which ensure optimal release of the active pharmaceutical ingredient. The study of the specific activity of the developed medicinal forms of vinpocetine was carried out on a model of acute cerebrovascular accident of the type of ischemic stroke. Vinpocetin tablets (Astrapharm, Ukraine), which are used in neurological practice quite effectively and over a long period of time, were used as a comparison drug. Results. The comparative results showed that the appointment of all studied drugs led to an increase in motor activity. In addition, the administration of medicinal forms of vinpocetine reduced the development of cognitive and cognitive disorders after acute disorders of cerebral blood circulation. It was found that the highest result was shown by the group of animals that received a course of vinpocetine intranasally. In the groups of animals that received vinpocetine for 4 days, markers of oxidative stress – aldehyde phenylhydrazones and ketone phenylhydrazones – were significantly reduced. The highest activity was demonstrated by the pharmaceutical form of vinpocetin, which was used intranasally for 4 days. The introduction of dosage forms of vinpocetine exerted an energizing effect, which was expressed in an increase in the level of macroergic phosphates. Evidently, vinpocetine has a direct positive effect on the three-carbon sections of the Krebs cycle and increases the production of adenosine triphosphate (ATP). At the same time, the vinpocetine nasal cream applied intranasally for 4 days demonstrated the greatest energizing activity. Conclusions. Preclinical studies of the developed application soft medicines with vinpocetine on the model of acute cerebrovascular accident type ischemic stroke experimentally confirmed the expressed neuroprotective activity of rectal suppositories and nasal cream with vinpocetine and it was found that the effectiveness of therapy with these application medicinal forms is demonstrably higher than that in comparison with oral tablet means.

Therapeutic Potential of Targeting Mitochondria for Alzheimer's Disease Treatment.

Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, is characterized by memory and cognitive impairment and by the accumulation in the brain of abnormal proteins, more precisely beta-amyloid (β-amyloid or Aβ) and Tau proteins. Studies aimed at researching pharmacological treatments against AD have focused precisely on molecules capable, in one way or another, of preventing/eliminating the accumulations of the aforementioned proteins. Unfortunately, more than 100 years after the discovery of the disease, there is still no effective therapy in modifying the biology behind AD and nipping the disease in the bud. This state of affairs has made neuroscientists suspicious, so much so that for several years the idea has gained ground that AD is not a direct neuropathological consequence taking place downstream of the deposition of the two toxic proteins, but rather a multifactorial disease, including mitochondrial dysfunction as an early event in the pathogenesis of AD, occurring even before clinical symptoms. This is the reason why the search for pharmacological agents capable of normalizing the functioning of these subcellular organelles of vital importance for nerve cells is certainly to be considered a promising approach to the design of effective neuroprotective drugs aimed at preserving this organelle to arrest or delay the progression of the disease. Here, our intent is to provide an updated overview of the mitochondrial alterations related to this disorder and of the therapeutic strategies (both natural and synthetic) targeting mitochondrial dysfunction.

The Neuroprotective Effects of Exosomes Derived from TSG101-Overexpressing Human Neural Stem Cells in a Stroke Model.

Although tissue-type plasminogen activator was approved by the FDA for early reperfusion of occluded vessels, there is a need for an effective neuroprotective drug for stroke patients. In this study, we established tumor susceptibility gene (TSG)101-overexpressing human neural stem cells (F3.TSG) and investigated whether they showed enhanced secretion of exosomes and whether treatment with exosomes during reperfusion alleviated ischemia-reperfusion-mediated brain damage. F3.TSG cells secreted higher amounts of exosomes than the parental F3 cells. In N2A cells subjected to oxygen–glucose deprivation (OGD), treatment with exosomes or coculture with F3.TSG cells significantly attenuated lactate dehydrogenase release, the mRNA expression of proinflammatory factors, and the protein expression of DNA-damage-related proteins. In a middle cerebral artery occlusion (MCAO) rat model, treatment with exosomes, F3 cells, or F3.TSG cells after 2 h of occlusion followed by reperfusion reduced the infarction volume and suppressed inflammatory cytokines, DNA-damage-related proteins, and glial fibrillary acidic protein, and upregulated several neurotrophic factors. Thus, TSG101-overexpressing neural stem cells showed enhanced exosome secretion; exosome treatment protected against MCAO-induced brain damage via anti-inflammatory activities, DNA damage pathway inhibition, and growth/trophic factor induction. Therefore, exosomes and F3.TSG cells can affect neuroprotection and functional recovery in acute stroke patients.

Uticaj lokalnih antiglaukomatoznih lekova na redukciju pada senzitivnosti vidnog polja usled druza glave vidnog živca - prikaz slučaja

Optic nerve head drusen are congenital anomalies of the optic nerve, a form of calcium degeneration of axons of the optic nerve head. Initially asymptomatic, drusen may be one of the causes of progressive optic neuropathy. They are clinically presented as acellular, hyaline deposits of globular appearance in prelaminar segment of the optic nerve head. They occure due to: altered axonal transport, small diameter of scleral channel, compression and ischemia. Frequent complications include progressive visual field defects, ischemic optic neuropathy, central retinal artery or vein occlusion, or peripapillar neovascularization. Diagnostic tools: ophthalmoscopy, angiography, computerized perimetry, B-scan ultrasonography, CT, OCT, HRT, GDx, electrophysiological testing. The treatment is medicamentous, laser, or surgery. Most of the pilot studies confirms the benefit of topical hypotensive drugs even when the drusen are not associated with glaucoma. The decrease of intraocular pressure reduces compression of the optic nerve axons and improves reperfusion. This paper presents a young patient with bilateral optic nerve head drusen, progressive scotoma and topical hypotensive medication administered. After six months, scotoma and the loss of sensitivity were reduced. The effect of neuroprotective drugs is researched to reduce potential morbidity.

Neuroprotective effects of some epigenetic modifying drugs' on Chlamydia pneumoniae-induced neuroinflammation: A novel model.

Chlamydia pneumoniae (Cpn) is a gram-negative intracellular pathogen that causes a variety of pulmonary diseases, and there is growing evidence that it may play a role in Alzheimer’s disease (AD) pathogenesis. Cpn can interact functionally with host histones, altering the host’s epigenetic regulatory system by introducing bacterial products into the host tissue and inducing a persistent inflammatory response. Because Cpn is difficult to propagate, isolate, and detect, a modified LPS-like neuroinflammation model was established using lyophilized cell free supernatant (CFS) obtained from infected cell cultures, and the effects of CFS were compared to LPS. The neuroprotective effects of Trichostatin A (TSA), givinostat, and RG108, which are effective on epigenetic mechanisms, and the antibiotic rifampin, were studied in this newly introduced model and in the presence of amyloid beta (Aβ) 1–42. The neuroprotective effects of the drugs, as well as the effects of CFS and LPS, were evaluated in Aβ-induced neurotoxicity using a real-time cell analysis system, total ROS, and apoptotic impact. TSA, RG108, givinostat, and rifampin all demonstrated neuroprotective effects in both this novel model and Aβ-induced neurotoxicity. The findings are expected to provide early evidence on neuroprotective actions against Cpn-induced neuroinflammation and Aβ-induced neurotoxicity, which could represent a new treatment option for AD, for which there are currently few treatment options.

L-Serine, an Endogenous Amino Acid, Is a Potential Neuroprotective Agent for Neurological Disease and Injury.

Central nervous system (CNS) lesions are major causes of human death and disability worldwide, and they cause different extents of motor and sensory dysfunction in patients. Thus, it is crucial to develop new effective neuroprotective drugs and approaches targeted to the heterogeneous nature of CNS injury and disease. L-serine is an indispensable neurotrophic factor and a precursor for neurotransmitters. Although L-serine is a native amino acid supplement, its metabolic products have been shown to be essential not only for cell proliferation but also for neuronal development and specific functions in the brain. Growing evidence has suggested that L-serine regulates the release of several cytokines in the brain under some neuropathological conditions to recover cognitive function, improve cerebral blood flow, inhibit inflammation, promote remyelination and exert other neuroprotective effects on neurological injury. L-serine has also been used to treat epilepsy, schizophrenia, psychosis, and Alzheimer’s Disease as well as other neurological diseases. Furthermore, the dosing of animals with L-serine and human clinical trials investigating the therapeutic effects of L-serine generally support the safety of L-serine. The high significance of this review lies in its emphasis on the therapeutic potential of using L-serine as a general treatment for numerous CNS diseases and injuries. Because L-serine performs a broad spectrum of functions, it may be clinically used as an effective neuroprotective agent.

Assessment of the Effects of Drugs on Mitochondrial Respiration.

Mitochondria are targets of newly synthesized drugs and being tested for the treatment of various diseases caused or accompanied by disruption of cellular bioenergetics. In drug development, it is necessary to test for drug-induced changes in mitochondrial enzyme activity that may be related to therapeutic or adverse drug effects. Measurement of drug effect on mitochondrial oxygen consumption kinetics and/or protective effects of drugs against calcium-induced inhibition of the mitochondrial respiration can be used for the study mitochondrial toxicity and neuroprotective effects of drugs. Supposing that the drug-induced inhibition of the mitochondrial respiratory rate and/or individual mitochondrial complexes is associated with adverse drug effects, the effects of drugs on mitochondrial respiration in isolated mitochondria allow selection of novel molecules that are relatively safe for mitochondrial toxicity.

Exosomes Derived from CXCR4-Overexpressing BMSC Promoted Activation of Microvascular Endothelial Cells in Cerebral Ischemia/Reperfusion Injury

Background Ischemic stroke is a severe acute cerebrovascular disease which can be improved with neuroprotective therapies at an early stage. However, due to the lack of effective neuroprotective drugs, most stroke patients have varying degrees of long-term disability. In the present study, we investigated the role of exosomes derived from CXCR4-overexpressing BMSCs in restoring vascular function and neural repair after ischemic cerebral infarction. Methods BMSCs were transfected with lentivirus encoded by CXCR4 (BMSCCXCR4). Exosomes derived from BMSCCXCR4 (ExoCXCR4) were isolated and characterized by transmission electron microscopy and dynamic light scattering. Western blot and qPCR were used to analyze the expression of CXCR4 in BMSCs and exosomes. The acute middle cerebral artery occlusion (MCAO) model was prepared, ExoCXCR4 were injected into the rats, and behavioral changes were analyzed. The role of ExoCXCR4 in promoting the proliferation and tube formation for angiogenesis and protecting brain endothelial cells was determined in vitro. Results Compared with the control groups, the ExoCXCR4 group showed a significantly lower mNSS score at 7 d, 14 d, and 21 d after ischemia/reperfusion (P < 0.05). The bEnd.3 cells in the ExoCXCR4 group have stronger proliferation ability than other groups (P < 0.05), while the CXCR4 inhibitor can reduce this effect. Exosomes control (ExoCon) can significantly promote the migration of bEnd.3 cells (P < 0.05), while there was no significant difference between the ExoCXCR4 and ExoCon groups (P > 0.05). ExoCXCR4 can further promote the proliferation and tube formation for the angiogenesis of the endothelium compared with ExoCon group (P < 0.05). In addition, cobalt chloride (COCl2) can increase the expression of β-catenin and Wnt-3, while ExoCon can reduce the expression of these proteins (P < 0.05). ExoCXCR4 can further attenuate the activation of Wnt-3a/β-catenin pathway (P < 0.05). Conclusions In ischemia/reperfusion injury, ExoCXCR4 promoted the proliferation and tube formation of microvascular endothelial cells and play an antiapoptotic role via the Wnt-3a/β-catenin pathway.

Hederagenin Attenuates Cerebral Ischaemia/Reperfusion Injury by Regulating MLK3 Signalling.

Cerebral ischaemia/reperfusion (CI/R) injury is a major challenge due to the lack of effective neuroprotective drugs. Hederagenin (HE) is the aglycone part of saponins extracted from Hedera helix Linné that has exhibited anti-apoptotic and anti-inflammatory effects; however, the role of HE in CI/R has not been elucidated. In this study, mice were intraperitoneally (i.p.) injected with HE (26.5, 53, or 106 μmol/kg body weight) for 3 days after middle cerebral artery occlusion (MCAO). Neural function and brain infarct volume were evaluated. HE treatment attenuated CI/R-induced apoptosis and inflammatory cytokine expression within the infarcted areas. HE treatment also decreased the activation of the MLK3 signalling pathway, which potentiates CI/R damage via the MAPK and NFκB pathways. Due to HE’s safety profile, it has potential to be used for the clinical treatment of ischaemic stroke.