Mesenchymal stem cell transplantation into the spinal cord of healthy adult horses undergoing cervical ventral interbody fusion.

OBJECTIVE: To determine the feasibility of umbilical cord-derived mesenchymal stem cell (UC-MSC) transplantation into the cervical spinal cord of horses by using fluoroscopy with or without endoscopic guidance and to evaluate the neurological signs and tissue reaction after injection. STUDY DESIGN: Experimental study. ANIMALS: Eight healthy adult horses with no clinical signs of neurological disease. METHODS: After cervical ventral interbody fusion (CVIF), ten million fluorescently labeled allogeneic UC-MSC were injected into the spinal cord under endoscopic and fluoroscopic guidance (n = 5) or fluoroscopic guidance only (n = 3). Postoperative neurological examinations were performed, and horses were humanely killed 48 hours (n = 4) or 14 days (n = 4) postoperatively. Spinal tissues were examined after gross dissection and with bright field and fluorescent microscopy. RESULTS: Needle endoscopy of the cervical canal by ventral approach was associated with intraoperative spinal cord puncture (2/5) and postoperative ataxia (3/5). No intraoperative complications occurred, and one (1/3) horse developed ataxia with cell transplantation under fluoroscopy alone. Umbilical cord-derived MSC were associated with small vessels and detected up to 14 days in the spinal cord. Demyelination was observed in six of eight cases. CONCLUSION: Fluoroscopically guided intramedullary UC-MSC transplantation during CVIF avoids spinal cord trauma and decreases risk of ataxia from endoscopy. Umbilical cord-derived MSC persist in the spinal cord for up to 14 days. Cell injection promotes angiogenesis and induces demyelination of the spinal tissue. CLINICAL SIGNIFICANCE: Umbilical cord-derived MSC transplantation into the spinal cord during CVIF without endoscopy is recommended for future evaluation of cell therapy in horses affected by cervical vertebral compressive myelopathy.

Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46-/- mice.

Mitochondrial disorders are the result of nuclear and mitochondrial DNA mutations that affect multiple organs, with the central and peripheral nervous system often affected. Currently, there is no cure for mitochondrial disorders. Currently, gene therapy offers a novel approach for treating monogenetic disorders, including nuclear genes associated with mitochondrial disorders. We utilized a mouse model carrying a knockout of the mitochondrial fusion-fission-related gene solute carrier family 25 member 46 (Slc25a46) and treated them with neurotrophic AAV-PHP.B vector carrying the mouse Slc25a46 coding sequence. Thereafter, we used immunofluorescence staining and western blot to test the transduction efficiency of this vector. Toluidine blue staining and electronic microscopy were utilized to assess the morphology of optic and sciatic nerves following treatment, and the morphology and respiratory chain activity of mitochondria within these tissues were determined as well. The adeno-associated virus (AAV) vector effectively transduced in the cerebrum, cerebellum, heart, liver and sciatic nerves. AAV-Slc25a46 treatment was able to rescue the premature death in the mutant mice (Slc25a46-/-). The treatment-improved electronic conductivity of the peripheral nerves increased mobility and restored mitochondrial complex activities. Most notably, mitochondrial morphology inside the tissues of both the central and peripheral nervous systems was normalized, and the neurodegeneration, chronic neuroinflammation and loss of Purkinje cell dendrites observed within the mutant mice were alleviated. Overall, our study shows that AAV-PHP.B's neurotrophic properties are plausible for treating conditions where the central nervous system is affected, such as many mitochondrial diseases, and that AAV-Slc25a46 could be a novel approach for treating SLC25A46-related mitochondrial disorders.

Clofibrate, a PPAR-α agonist, abrogates sodium fluoride-induced neuroinflammation, oxidative stress, and motor incoordination via modulation of GFAP/Iba-1/anti-calbindin signaling pathways.

Fluoride is an environmental contaminant that is ubiquitously present in air, water, and soil. It is commonly added in minute quantity to drinking water, toothpaste, and mouth rinses to prevent tooth decay. Epidemiological findings have demonstrated that exposure to fluoride induced neurodevelopmental toxicity, developmental neurotoxicity, and motor disorders. The neuroprotective effect of clofibrate, a peroxisome proliferator-activated receptor alpha agonist, was investigated in the present study. Forty male Wistar rats were used for this study and randomly grouped into 10 rats per group as control, sodium fluoride (NaF) alone (300 ppm), NaF plus clofibrate (250 mg/kg), and NaF plus lisinopril (10 mg/kg), respectively, for 7 days. NaF was administered in drinking water while clofibrate and lisinopril were administered by oral gavage. Markers of neuronal inflammation and oxidative stress, acetylcholinesterase activity, and neurobehavioral (hanging wire and open field) tests were performed. Immunohistochemistry was performed on brain tissues, and they were probed with glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, and cerebellar Ca2+ -binding protein calbindin-D28k. The results showed that NaF significantly increased of oxidative stress and neuroinflammation and inhibited AChE activity. Immunostaining showed reactive astrocytes, microgliosis, loss of dendritic spines, and arborization in Purkinje cells in rats administered only NaF. Neurobehavioral results showed that cotreatment of NaF with clofibrate improved muscular strength and locomotion, reduced anxiety, and significantly reduced astrocytic count. Overall, cotreatment of NaF with either clofibrate or lisinopril showed neuroprotective effects by mitigating neuronal inflammation and oxidative and motor incoordination. Hence, clofibrate could be seen as a novel drug candidate against neurodegeneration and motor disorders.

Tocopherols, tocotrienols and tocomonoenols: Many similar molecules but only one vitamin E.

The aim of this article is to correct a very general error in scientific articles, in textbooks and in the Internet that has become an accepted fact. In this literature, the term "vitamin E″ is used for several similar molecules (both tocopherols and tocotrienols) that have never been shown to have vitamin property, i.e. a protective effect against the human deficiency disease. In fact, the name "vitamin E″ should only be used to define molecules that prevent the human deficiency disease "Ataxia with Vitamin E Deficiency" (AVED). Only one such molecule is known, α-tocopherol. This error may confuse consumers as well as medical doctors, who prescribe vitamin E without realizing that the current use of the name includes molecules of unknown, if not unwanted functions.

Treatment with potassium bromide mitigates ataxia and reduces tremor in lambs with perennial ryegrass toxicosis.

Aims: To assess the use of potassium bromide (KBr) as a therapeutic intervention for perennial ryegrass toxicosis (PRGT) in lambs fed ryegrass seed containing lolitrem B. Methods: Male lambs aged 10-12 months (n = 43) were assigned to receive ryegrass seed containing lolitrem B, at a dose of 0.16 mg/kg/day (Groups 2, 3 and 4), or lucerne chaff and molasses (Groups 1 and 5). Lambs in Groups 2 and 3 were observed for clinical signs and gait changes until defined signs of PGRT were observed, when they were transferred, with lambs in Group 1, to the Testing phase of the trial. Lambs in Group 3 were then treated with a single oral dose of 300 mg/kg bromide. Lambs in Groups 4 and 5 received KBr daily from the start of the trial (540 mg/kg bromide over 3 days then 20 mg/kg daily) and were transferred to the Testing phase after 18 days. Clinical examination and gait assessment, and surface electromyography of the triceps muscle, measuring root-mean-square (RMS) voltages, were carried out on Days 0, 1 and 2 of the Testing phase followed by necropsy, histopathology, measurement of concentrations of bromide in serum and CSF and faecal cortisol metabolites (FCM). Results: In Group 3 lambs, mean composite gait scores decreased between Testing phase Day 0 and Days 1 and 2 (p < 0.001), but increased in lambs in Group 2 between Day 0 and Day 2 (p = 0.015). Scores for lambs in Group 3 on Day 2 were lower than for lambs in Group 2 (p < 0.001). Mean RMS voltages on Day 2 were higher in lambs in Group 2 than Group 3 (p = 0.045). Mean concentrations of bromide in serum were >800 µg/mL in lambs in Groups 3 and 4 on Day 2. Concentrations of FCM were higher in lambs from Group 2 than in Groups 1 or 5, but were similar in Groups 2, 3 and 4. Histopathological findings in the cerebellum of lambs from Groups 2, 3 and 4 were similar, showing pyknosis of neurons within the granular layer of the cerebellum and Purkinje neuron proximal axonal spheroid formation. Conclusions and clinical relevance: A single oral dose of 300 mg/kg bromide in lambs with neurological signs of PRGT resulted in reduced composite gait scores and reduced RMS voltages, indicating a significant improvement in clinical signs of ataxia, movement disorder and muscle tremor associated with the neurotoxic effects of lolitrem B.

Chiari Malformation Type 1: A Systematic Review of Natural History and Conservative Management.

BACKGROUND: Chiari malformation type 1 (CM-1) is a variation of hindbrain development that can sometimes occur in asymptomatic individuals. Conventional treatment is surgical decompression, but little is known about the natural history of patients who do not undergo surgical management. This information is critical to determine how these patients should be managed. We conducted a systematic literature review to determine the natural history of CM-1, particularly in patients who did not undergo surgery and in asymptomatic individuals, to help patients and physicians determine when surgery is likely to be beneficial. METHODS: The literature search was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the electronic databases PubMed, Scopus, Cochrane Library, and Web of Science. Inclusion and exclusion criteria were predefined. RESULTS: In symptomatic patients who did not undergo surgery, headaches and nausea often improved, whereas ataxia and sensory disturbance tended not to improve spontaneously. Of patients, 27%-47% had an improvement in symptoms after 15 months, and 37%-40% with cough headache and 89% with nausea who were managed nonoperatively improved at follow-up. Most asymptomatic individuals with CM-1 remained asymptomatic (93.3%) even in the presence of syringomyelia. CONCLUSIONS: The natural history of mild symptomatic and asymptomatic CM-1 in adults is relatively benign and nonprogressive; the decision to perform surgical decompression should be based on severity and duration of a patient's symptoms at presentation. It is reasonable to observe a patient with mild or asymptomatic symptoms even in the presence of significant tonsillar descent or syringomyelia.

[Functional Electrical Stimulation in a Case of Drop Foot and Atactic Gait: Expert Assessment of Contested Medical Aids]. / Funktionelle Elektrostimulation bei Fußheberschwäche und ataktischem Gangbild: Gutachterliches Vorgehen bei streitiger Hilfsmittelversorgung.

Expert medical opinions are necessary in pretrial cases and other legal matters. They act as means of evidence for administrative bodies and courts. It may be necessary to adapt the method of evaluation depending upon the issue or subject matter to be evaluated. We report on a social court case, which needed to answer the question of the medical necessity of a functional electrical stimulation orthosis prescribed to improve the function of a drop foot accompanied by an atactic gait disorder. The claimant suffered from a stroke, which had occurred several years before. Her aids were an ankle-foot-orthosis for foot lift and a wheeled walker. The current treatment was to be augmented by the disputed device. The statutory health insurance declined to meet the costs. They failed to find relevant benefits after analysis of video tapes of the patient's gait while using an electrical stimulation orthosis. The social court requested an expert opinion to answer the question as to whether or not there was a relevant functional benefit to using functional electrical stimulation over the existing orthosis or to an alternative treatment. Video documentation was desired by the court. We used the clinic's gait analysis laboratory, which is equipped with a gait course and the claimed video documentation. Standardised video documentation offers substantial advantages for answering forensic questions such as these. It assures reproducibility and comparability of all tested scenarios, with objectification of the individual advantages or limitations. This gain in both validity and reliability fulfills the scientific requirements placed upon an expert assessment.

Viewing 3D TV over two months produces no discernible effects on balance, coordination or eyesight.

With the rise in stereoscopic 3D media, there has been concern that viewing stereoscopic 3D (S3D) content could have long-term adverse effects, but little data are available. In the first study to address this, 28 households who did not currently own a 3D TV were given a new TV set, either S3D or 2D. The 116 members of these households all underwent tests of balance, coordination and eyesight, both before they received their new TV set, and after they had owned it for 2 months. We did not detect any changes which appeared to be associated with viewing 3D TV. We conclude that viewing 3D TV does not produce detectable effects on balance, coordination or eyesight over the timescale studied. Practitioner Summary: Concern has been expressed over possible long-term effects of stereoscopic 3D (S3D). We looked for any changes in vision, balance and coordination associated with normal home S3D TV viewing in the 2 months after first acquiring a 3D TV. We find no evidence of any changes over this timescale.

Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression.

UNLABELLED: Although the initial concepts of stem cell therapy aimed at replacing lost tissue, more recent evidence has suggested that stem and progenitor cells alike promote postischemic neurological recovery by secreted factors that restore the injured brain's capacity to reshape. Specifically, extracellular vesicles (EVs) derived from stem cells such as exosomes have recently been suggested to mediate restorative stem cell effects. In order to define whether EVs indeed improve postischemic neurological impairment and brain remodeling, we systematically compared the effects of mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) with MSCs that were i.v. delivered to mice on days 1, 3, and 5 (MSC-EVs) or on day 1 (MSCs) after focal cerebral ischemia in C57BL6 mice. For as long as 28 days after stroke, motor coordination deficits, histological brain injury, immune responses in the peripheral blood and brain, and cerebral angiogenesis and neurogenesis were analyzed. Improved neurological impairment and long-term neuroprotection associated with enhanced angioneurogenesis were noticed in stroke mice receiving EVs from two different bone marrow-derived MSC lineages. MSC-EV administration closely resembled responses to MSCs and persisted throughout the observation period. Although cerebral immune cell infiltration was not affected by MSC-EVs, postischemic immunosuppression (i.e., B-cell, natural killer cell, and T-cell lymphopenia) was attenuated in the peripheral blood at 6 days after ischemia, providing an appropriate external milieu for successful brain remodeling. Because MSC-EVs have recently been shown to be apparently safe in humans, the present study provides clinically relevant evidence warranting rapid proof-of-concept studies in stroke patients. SIGNIFICANCE: Transplantation of mesenchymal stem cells (MSCs) offers an interesting adjuvant approach next to thrombolysis for treatment of ischemic stroke. However, MSCs are not integrated into residing neural networks but act indirectly, inducing neuroprotection and promoting neuroregeneration. Although the mechanisms by which MSCs act are still elusive, recent evidence has suggested that extracellular vesicles (EVs) might be responsible for MSC-induced effects under physiological and pathological conditions. The present study has demonstrated that EVs are not inferior to MSCs in a rodent stroke model. EVs induce long-term neuroprotection, promote neuroregeneration and neurological recovery, and modulate peripheral post-stroke immune responses. Also, because EVs are well-tolerated in humans, as previously reported, the administration of EVs under clinical settings might set the path for a novel and innovative therapeutic stroke concept without the putative side effects attached to stem cell transplantation.

Sensitization and Tolerance Following Repeated Exposure to Caffeine and Alcohol in Mice.

BACKGROUND: Energy drinks are popular mixers with alcohol. While energy drinks contain many ingredients, caffeine is an important pharmacologically active component and is generally present in larger amounts than in other caffeinated beverages. In these studies, we investigated the hypothesis that caffeine would influence the effects of alcohol (ethanol [EtOH]) on conditioned taste aversion (CTA), ataxia, and locomotor activity (LA) after repeated exposure. METHODS: Four groups of mice were exposed by oral gavage twice daily to vehicle, EtOH (4 g/kg), caffeine (15 mg/kg), or the EtOH/caffeine combination. CTA to saccharin and ataxia in the parallel rod task was evaluated after 8 or 16 gavages, respectively, using EtOH (1 to 3 g/kg) or EtOH/caffeine (3 mg/kg + 2 g/kg) challenges. In addition, LA was evaluated initially and after repeated exposure to oral gavage of these drugs and doses. RESULTS: Repeated oral gavage of EtOH produced significant locomotor sensitization, with those mice increasing total distance traveled by 2-fold. The locomotor response to caffeine, while significantly greater than vehicle gavage, did not change with repeated exposure. On the other hand, repeated gavage of caffeine/EtOH combination produced a substantial increase in total distance traveled after repeated exposure (~4-fold increase). After repeated EtOH exposure, there was significant tolerance to EtOH in the CTA and parallel rod tests. However, neither a history of caffeine exposure nor including caffeine influenced EtOH-induced CTA. Interestingly, a history of caffeine exposure increased the ataxic response to the caffeine/EtOH combination and appeared to reduce the ataxic response to high doses of EtOH. CONCLUSIONS: The data support the general hypothesis that repeated exposure to caffeine influences the response to EtOH. Together with previously published work, these data indicate that caffeine influences some EtOH-related behaviors, notably locomotion and ataxia, but appears not to influence the expression of conditioned behaviors.

Influence of arachidonyl-2'-chloroethylamide, a selective cannabinoid CB1 receptor agonist, on the anticonvulsant and acute side-effect potentials of clobazam, lacosamide, and pregabalin in the maximal electroshock-induced seizure model and chimney test in mice.

The influence of arachidonyl-2'-chloroethylamide (ACEA - a selective cannabinoid CB1 receptor agonist) on the anticonvulsant potency and acute adverse-effect potentials of clobazam, lacosamide, and pregabalin was determined in the maximal electroshock-induced seizure model and chimney test in mice. ACEA (2.5 mg/kg, i.p.) significantly enhanced the anticonvulsant potency of pregabalin in the mouse maximal electroshock-induced seizure model by decreasing the median effective dose (ED50 ) of pregabalin from 125.39 to 78.06 mg/kg (P < 0.05). In contrast, ACEA (2.5 mg/kg) had no significant impact on the anticonvulsant potency of clobazam and lacosamide in the mouse maximal electroshock-induced seizure model. On the other hand, ACEA (2.5 mg/kg) did not affect acute adverse effects of clobazam, lacosamide or pregabalin, and the median toxic doses (TD50 ) for the studied anti-epileptic drugs in combination with ACEA did not differ from the TD50 values as determined for the drugs administered alone in the chimney test. In conclusion, ACEA ameliorates the pharmacological profile of pregabalin, when considering both the anticonvulsant and the acute adverse effects of the drug in preclinical study on animals. The combination of pregabalin with ACEA can be of pivotal importance for patients with epilepsy as a potentially advantageous combination if the results from this study translate into clinical settings.

Selenium and coenzyme Q10 interrelationship in cardiovascular diseases--A clinician's point of view.

A short review is given of the potential role of selenium deficiency and selenium intervention trials in atherosclerotic heart disease. Selenium is an essential constituent of several proteins, including the glutathione peroxidases and selenoprotein P. The selenium intake in Europe is generally in the lower margin of recommendations from authorities. Segments of populations in Europe may thus have a deficient intake that may be presented by a deficient anti-oxidative capacity in various illnesses, in particular atherosclerotic disease, and this may influence the prognosis of the disease. Ischemic heart disease and heart failure are two conditions where increased oxidative stress has been convincingly demonstrated. Some of the intervention studies of anti-oxidative substances that have focused on selenium are discussed in this review. The interrelationship between selenium and coenzyme Q10, another anti-oxidant, is presented, pointing to a theoretical advantage in using both substances in an intervention if there are deficiencies within the population. Clinical results from an intervention study using both selenium and coenzyme Q10 in an elderly population are discussed, where reduction in cardiovascular mortality, a better cardiac function according to echocardiography, and finally a lower concentration of the biomarker NT-proBNP as a sign of lower myocardial wall tension could be seen in those on active treatment, compared to placebo.

[THYMIC HORMONES, ANTIOXIDANT ENZYMES AND NEUROGENESIS OF BULBUS OLFACTORIUS IN RATS WITH PARKINSONISM: THE EFFECT OF MELATONIN].

The adult rats received both neurotoxin 6-hidroxidophamine and neurotoxin and melatonin. It was investigated a link between the disturbances of the brain antioxidant enzymes activity and thymic endocrine function, as possible pathogenic factors of parkinsonism, with changes in the number of neural stem cells (NSC) in the bulbus olfactorius. Rats with motor asymmetry in the apomorphine test and significant damage of the dopaminergic neurons in the-substantia nigra have decreased levels of superoxide dismutase, catalase and glutathione peroxidase activities in striatum (1.3-1.4 times) and blood thymulin content (8 times) compared to control group. On the contrary, examined indices were not changed in rats without motor asymmetry and correspondingly partly damaged neurons. The number of nestin(+)-cells in the bulbus olfactorius of rats without motor asymmetry increased from 91.2% to 99.3% and remained unchanged after melatonin administration course (10 mg/kg during 18 days). Melatonin administration resulted in the decrease in the number of nestin(+)-cells along with significant elevation of the decreased antioxidant enzymes activity and blood thymulin content in rats with circulatory movements. Possibilities of the enhancement of NSC differentiation in bulbus olfactorius into neuronal direction in such animals has been discussed. The conclusion about the potential use of melatonin as a neuroprotector in parkinsonism therapy has been made.

Intermittent prophylaxis of recurrent febrile seizures with clobazam versus diazepam.

Febrile seizures are the most common type of seizure among children that can be prevented by using prophylactic drugs like Clobazam and Diazepam. The present prospective study was conducted in the Department of Pediatrics, Mymensingh Medical College Hospital and Community Based Medical College Hospital, Bangladesh over a period of 1 year from July 2012 to June 2013 to compare the effectiveness of intermittent Clobazam versus Diazepam therapy in preventing the recurrence of febrile seizures and assessed adverse effects of each drug. A total of 65 patients (32 children administered Clobazam and rest 33 children received Diazepam) of simple and complex febrile seizures aged 6 months to 5 years of both sexes were the study population. Data were collected by interview of the patients, clinical examination and laboratory investigations using the research instrument. Data were analyzed by using Chi-square (χ2) Test, Student's 't' Test and Fisher's Exact Test. For all analytical tests, the level of significance was set at 0.05 and p<0.05 was considered significant. The proportion of patients was higher between age 12-36 months and male was predominant in the both Clobazam and Diazepam groups. Over 31% of patients in Clobazam group who experienced episode of fever within 3 months, 40.6% within 6 months and 9.4% within 9 months compared to 36.4% in Diazepam group within 3 months, 45.5% within 6 months & 12.1% within 9 months after discharge from the hospital. Three (9.4%) patients in Clobazam group and 7(21.3%) in Diazepam group who experienced febrile convulsion during the follow up period. From the data adverse effects within 3 and 6 months experienced by the patient's drowsiness, sedation and ataxia were higher in Diazepam group than those in Clobazam group. However, within 9 months lethargy and irritability were somewhat higher in Clobazam group than those in Diazepam group. The mean duration of hospitalization was significantly higher in Diazepam group compared to Clobazam group (6.0±1.0 vs. 4.6±0.08 days, P<0.001). Seven (21.2%) out of 33 children with febrile seizures in Diazepam group had a history of recurrent seizures, whereas 3(9.4%) of 32 children in the Clobazam group. The risks of recurrent febrile seizure in the Diazepam group was 2.6 times greater compared to those in the Clobazam group (P=0.186). The result indicates that Clobazam is safe, efficacious, requires less frequent dosing and has less adverse effects such as drowsiness, sedation, ataxia and irritability as compared to Diazepam. So, Clobazam may be an alternative to Diazepam given intermittently for prevention of recurrent febrile seizures.

Gastrodin prevents motor deficits and oxidative stress in the MPTP mouse model of Parkinson's disease: involvement of ERK1/2-Nrf2 signaling pathway.

AIMS: Current no effective therapy is available to halt the progression of Parkinson's disease (PD). Oxidative stress has been implicated in the etiology of PD. The present study evaluates the hypothesis that prevention of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor deficits by gastrodin might mainly result from its antioxidant property via interrupting extracellular signal regulated protein kinases (ERK) 1/2-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. MAIN METHODS: Pretreatment of mouse model of PD is established by treating C57BL/6 mice with 4 doses of MPTP (30 mg/kg per day, i.p.), with gastrodin (60 mg/kg per day) administered by daily intraperitoneal injection for 2 weeks. Motor behavior of mice was monitored by open-field test and rotarod test. Real-time polymerase chain reaction and Western blotting were used to analyze the expression of genes. KEY FINDINGS: MPTP-induced motor deficits were partially and significantly forestalled by gastrodin. Gastrodin treatment prevented MPTP-induced oxidative stress, as measured by malondialdehyde in midbrain. Interestingly, MPTP-intoxicated mice treated with gastrodin robustly increased heme oxygenase 1, superoxide dismutase, glutathione levels, and Nrf2 nuclear translocation in striatum of MPTP-intoxicated mice. Furthermore, results herein suggest that the antioxidant pathway activated by gastrodin involves ERK1/2 phosphorylation. SIGNIFICANCE: Gastrodin protects midbrain of MPTP-intoxicated mice against oxidative stress, in part, through interrupting ERK1/2-Nrf2 pathway mechanism, which will give us an insight into the potential of gastrodin in terms of opening up new therapeutic avenues for PD.

The neuroprotective effects of isoflurane preconditioning in a murine transient global cerebral ischemia-reperfusion model: the role of the Notch signaling pathway.

Inhalational anesthetic preconditioning can induce neuroprotective effects, and the notch signaling pathway plays an important role in neural progenitor cell differentiation and the inflammatory response after central nervous system injury. This study evaluated whether the neuroprotective effect of isoflurane preconditioning is mediated by the activation of the notch signaling pathway. Mice were divided into two groups consisting of those that did or did not receive preconditioning with isoflurane. The expression levels of notch-1, notch intracellular domain (NICD), and hairy and enhancer of split (HES-1) were measured in mice subjected to transient global cerebral ischemia-reperfusion injury. The notch signaling inhibitor DAPT and conditional notch-RBP-J knockout mice were used to investigate the mechanisms of isoflurane preconditioning-induced neuroprotection. Immunohistochemical staining, real-time polymerase chain reaction assays, and Western blotting were performed. Isoflurane preconditioning induced neuroprotection against global cerebral ischemia. Preconditioning up-regulated the expression of notch-1, HES-1, and NICD after ischemic-reperfusion. However, these molecules were down-regulated at 72 h after ischemic-reperfusion. The inhibition of notch signaling activity by DAPT significantly attenuated the isoflurane preconditioning-induced neuroprotection, and similar results were obtained using notch knockout mice. Our results demonstrate that the neuroprotective effects of isoflurane preconditioning are mediated by the pre-activation of the notch signaling pathway.

[Nicotine and neurologic diseases--even a noxious substance may possess beneficial properties]. / Nikotiini ja neurologiset sairaudet--haitallisellakin aineella voi olla hyödyllisiä ominaisuuksia.

According to investigations, nicotine and its agonists may prevent the development of Parkinson's disease and reduce motor symptoms and dyskinesias in Parkinson's disease. It was shown recently that a transdermal nicotine patch reliefs the symptoms in patients suffering from mild cognitive impairment. In Alzheimer's disease an alpha7-selective agonist has been found to have positive effects on cognitive symptoms. Mutations of nicotinic receptors are underlying certain nocturnal frontal lobe epilepsies. The partial nicotine agonist varenicline may alleviate ataxia symptoms.

Neuroprotection by tetrahydroxystilbene glucoside in the MPTP mouse model of Parkinson's disease.

Our in vitro experiments suggested that tetrahydroxystilbene glucoside (TSG) affords a significant neuroprotective effect against MPP⁺-induced damage and apoptosis in PC12 cells though activation of the PI3K/Akt pathway. This study was aimed to investigate the potential neuroprotective effect of TSG in 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP)-treated mouse model of Parkinson's disease (PD). We found that treatment of TSG protected dopaminergic neurons by preventing MPTP-induced decreases in substantia nigra tyrosine hydroxylase (TH)-positive cells and striatal dopaminergic transporter (DAT) protein levels. Furthermore, it was also associated with increasing striatal Akt and GSK3ß phosphorylation, up-regulation of the Bcl-2/BAD ratio, and inhibition of the activation of caspase-9 and caspase-3. These results showed that TSG promoted dopamine neuron survival in vivo, the PI3K/Akt signaling pathway may have mediated the protection of TSG against MPTP, suggesting that TSG treatment might represent a neuroprotective treatment for PD.

Inhibition of 5-lipoxygenase activity in mice during cuprizone-induced demyelination attenuates neuroinflammation, motor dysfunction and axonal damage.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Increased expression of 5-lipoxygenase (5-LO), a key enzyme in the biosynthesis of leukotrienes (LTs), has been reported in MS lesions and LT levels are elevated in the cerebrospinal fluid of MS patients. To determine whether pharmacological inhibition of 5-LO attenuates demyelination, MK886, a 5-LO inhibitor, was given to mice fed with cuprizone. Gene and protein expression of 5-LO were increased at the peak of cuprizone-induced demyelination. Although MK886 did not attenuate cuprizone-induced demyelination in the corpus callosum or in the cortex, it attenuated cuprizone-induced axonal damage and motor deficits and reduced microglial activation and IL-6 production. These data suggest that during cuprizone-induced demyelination, the 5-LO pathway contributes to microglial activation and neuroinflammation and to axonal damage resulting in motor dysfunction. Thus, 5-LO inhibition may be a useful therapeutic treatment in demyelinating diseases of the CNS.