Effects of a Supplement Containing Cannabidiol (CBD) on Sedation and Ataxia Scores and Health.

Supplements containing Cannabidiol (CBD) are available for horses, however, few studies have been published on their effects on behavior and health parameters. The purpose of this study was to determine if a daily oral supplement containing CBD would cause sedation, ataxia or alterations in other health parameters during administration for 56 days. Twenty clinically healthy adult Thoroughbred horses were housed in stalls. Before treatment was initiated, a complete physical examination, complete blood count (CBC) and biochemical panel were evaluated. In addition, horses were examined for sedation and ataxia using standard scoring systems. Horses were randomly divided into two treatment groups, treated (supplement pellets containing CBD as Hemp Extract, 150 mg) or control (supplement pellets without CBD). Horses were treated daily and sedation and ataxia scores were assigned by two masked observers once weekly for 56 days. Horses were monitored daily for clinical signs or adverse events and body weights were recorded weekly. A CBC and biochemical panel were repeated on days 28 and 56, two hours after administration of the supplement. The supplement was readily consumed by the horses and no adverse effects were seen over the treatment period. Sedation and ataxia scores ranged from zero to two for all horses during the weekly examinations and there was no statistical difference between treatment groups. There were no treatment effects on blood values, including indicators of anemia and blood proteins, liver enzymes, kidney values, electrolytes or calcium. Body weight significantly increased in all horses, by Day 56 compared to Day zero but no treatment by day effect was noted. The CBD supplement (150 mg) was readily consumed and safe and did not result in changes in mentation, gait, or other health parameters, and no adverse clinical signs were observed during 56 days of oral administration.

Screening of Some Novel 4, 5 Disubstituted 1, 2, 4-Triazole-3-thiones for Anticonvulsant Activity.

OBJECTIVE: In the present study, we synthesized fifteen 4, 5-disubstituted 1, 2, 4-triazol- 3-thione derivatives and evaluated for anticonvulsant activity with neurotoxicity determination. METHODS: The synthesized compounds were characterized using FTIR, 1H-NMR and MS. The molecular docking study was also performed to study the interactions of compounds with LYS329 residue of gamma amino butyric acid aminotransferase (GABA-AT) using Autodock 4.2 software. The anticonvulsant activity was assessed by maximal electroshock (MES) test and subcutaneous pentylenetetrazol (scPTZ) tests. The neurotoxicity was assessed by rotarod ataxia test. RESULTS: In MES test, compounds 5a, 8a and 9a were found active at 100 mg/kg and five compounds were found active at 300 mg/kg dose after 1 hr of administration. After 4 hr of drug administration, only two compounds 8a and 9a exhibited protection at 100 mg/kg. In scPTZ test, three compounds 2a, 6a and 8a were found active at 100 mg/kg and 7a was active at 300 mg/kg after 1 hr of test drug administration. Most of the compounds were found active in MES test with 8a and 9a being the most active among all. In docking study, 2a was found to be best compound based on the binding energy of -6.5 kcal/mol and estimated inhibition constant of 17.2 µM. CONCLUSION: Majority of synthesized compounds were found active in MES test, whereas only few were found to possess anti scPTZ activity. Among all compounds, only 14a caused motor coordination impairment in rotarod ataxia test at 300 mg/kg 1 hr duration.

Methotrexate-induced Acute Myelopathy in a Teenager With High-risk Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is one of the most frequent malignancies in childhood whose long-term survival has increased up to 80% thanks to modern therapy enhancements. Nevertheless, methotrexate (MTX) remains a mainstay of ALL therapy, but also represents one of the major causes of neurotoxicity in patients with ALL. MTX-induced toxicity occurs in about 9% of patients treated for ALL. It usually affects deep white matter region leading to leukoencephalopathy, which has varying clinical manifestations ranging from acute neurologic disturbances to seizures or chronic permanent encephalopathy. Here we describe a 13-year-old girl affected with ALL who developed lower limbs hypesthesia and static ataxia due to transverse myelopathy after intrathec administration of MTX therapy. A high-dose corticotherapy combined to vitamin supplementation and rehabilitation was tested. Neurological evolution was characterized by slow and partial recovery.

Regressive pyridoxine-induced sensory neuronopathy in a patient with homocystinuria.

Pyridoxine (vitamin B6) is an essential vitamin playing a crucial role in amino acid metabolism. Pyridoxine is used for isoniazid side-effects prevention, pyridoxine-dependent epilepsy treatment and cystathionine beta-synthase deficiency (homocystinuria) treatment. However, vitamin B6 hypervitaminosis is neurotoxic and may provoke a progressive sensory neuronopathy (sensory ganglionopathy), usually when daily uptake is above 50 mg. We describe the case of a 30-year-old patient with homocystinuria who was treated with pyridoxine 1250-1750 mg/day for 20 years and developed progressive sensory neuropathy with ataxia and impaired sensation in the extremities. Electrodiagnostic testing demonstrated non-length-dependent abnormalities of sensory nerve potentials, and sensory ganglionopathy was diagnosed. Pyridoxine dosage was reduced to 500 mg/day, resulting in the disappearance of sensory symptoms and ataxia, and the normalisation of sensory nerve potentials. Our case indicates that pyridoxine-induced sensory ganglionopathy may be reversible, even after prolonged ingestion of high doses of vitamin B6 for more than 20 years.

No laughing matter: subacute degeneration of the spinal cord due to nitrous oxide inhalation.

BACKGROUND: Whilst the dangers of 'legal highs' have been widely publicised in the media, very few cases of the neurological syndrome associated with the inhalation of nitrous oxide (N2O) have been reported. Here we set out to raise awareness of subacute degeneration of the spinal cord arising from recreational N2O use so that formal surveillance programs and public health interventions can be designed. METHODS: Case series documenting the clinical and investigational features of ten consecutive cases of subacute degeneration of the spinal cord presenting to a hospital with a tertiary neurosciences service in East London. RESULTS: Sensory disturbance in the lower (± upper) limbs was the commonest presenting feature, along with gait abnormalities and sensory ataxia. MRI imaging of the spine showed the characteristic features of dorsal column hyperintensity on T2 weighted sequences. Serum B12 levels may be normal because subacute degeneration of the spinal cord in this situation is triggered by functional rather than absolute B12 deficiency. DISCUSSION: A high index of suspicion is required to prompt appropriate investigation, make the diagnosis and commence treatment early. This is the largest reported series of patients with subacute degeneration of the spinal cord induced by recreational use of N2O. However, the number of patients admitted to hospital likely represents the 'tip of the iceberg', with many less severe presentations remaining undetected. After raising awareness, attention should focus on measuring the extent of the problem, the groups affected, and devising ways to prevent potentially long-term neurological damage.

The Last Laugh - Reversible myeloneuropathy induced by chronic nitrous oxide use.

A previously fit and well 19 year old male presents with a progressive ataxic - sensory neuropathy worsening over 2 - 3 weeks. History and investigations revealed extensive recreational use of nitrous oxide resulting in functional B12 deficiency and consequent subacute combined degeneration of the cord. Abstinence and B12 supplementation resulted in a rapid and full neurological recovery. This case report highlights the importance of considering nitrous oxide abuse in the differential diagnosis of atypical neurological symptoms and signs, and emphasizes the possibility of good clinical outcomes with treatment.

Fatal Meningitis in Swine after Intrathecal Administration of Adeno-associated Virus Expressing Syngeneic Interleukin-10.

Interleukin-10 (IL-10) delivered by intrathecal (i.t.) gene vectors is a candidate investigational new drug (IND) for several chronic neurological disorders such as neuropathic pain. We performed a preclinical safety study of IL-10. A syngeneic large animal model was used delivering porcine IL-10 (pIL-10) to the i.t. space in swine by adeno-associated virus serotype 8 (AAV8), a gene vector that was previously found to be nontoxic in the i.t. space. Unexpectedly, animals became ill, developing ataxia, seizures, and an inability to feed and drink, and required euthanasia. Necropsy demonstrated lymphocytic meningitis without evidence of infection in the presence of normal laboratory findings for body fluids and normal histopathology of peripheral organs. Results were replicated in a second animal cohort by a team of independent experimenters. An extensive infectious disease and neuropathology workup consisting of comprehensive testing of tissues and body fluids in a specialized research veterinary pathology environment did not identify a pathogen. These observations raise the concern that i.t. IL-10 therapy may not be benign, that previously used xenogeneic models testing the human homolog of IL-10 may not have been sensitive enough to detect toxicity, and that additional preclinical studies may be needed before clinical testing of IL-10 can be considered.

Pyridoxine-induced sensory ataxic neuronopathy and neuropathy: revisited.

High dose pyridoxine is neurotoxic. Previous case reports were sparse and little is known about the clinical and electrodiagnostic findings. Three patients with pyridoxine-induced sensory ataxic neuropathy were studied and a review of the involved literature was performed. Three patients, aged 80, 83 and 83 years old, presented with sensory ataxia for 3-8 months. Examination showed signs of polyneuropathy and sensory ataxia. Six hundred milligrams of pyridoxine was consumed each day for 3-10 years, in the form of vitamin B1-6-12 combination tablet. Investigations for other causes of neuropathy were unremarkable. Blood levels of vitamin B6 were markedly elevated at 104.6, 81.4 and 66.9 times of upper normal limits. Electrodiagnostic tests showed symmetric axonal sensory polyneuropathy in two patients. Two years after vitamin discontinuation, all patients showed no significant improvement in the neuropathy and gait. In conclusion, consumption of high dose pyridoxine can cause sensory neuronopathy and axonal sensorimotor polyneuropathy, leading to sensory ataxia which may not be reversible.

Effects of Sceletium tortuosum in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Broad historical and current uses in addition to diverse activity on CNS targets may make Sceletium tortuosum a useful therapeutic in a variety of clinical settings. This study sought to more broadly characterize activity of Sceletium tortuosum and mesembrine in a number of common, rodent-based assays that model nociception, depression, anxiety, ataxia, and abuse liability. MATERIALS AND METHODS: Male Sprague-Dawley were administered Sceletium tortuosum extract products and behavioral responses were evaluated in the conditioned place preference (CPP), hot plate, forced swim, elevated plus, and rotarod tests. RESULTS AND CONCLUSIONS: Sceletium tortuosum does not cause preference or aversion in CPP. Mesembrine appears to have analgesic properties without abuse liabilities or ataxia. The Sceletium tortuosum fraction has antidepressant properties but does produce ataxia. The ataxia may limit its usefulness as an antidepressant unless the antidepressant activity is associated with one constituent and the ataxia is associated with a separate constituent.

Nitrogen-bisphosphonate therapy is linked to compromised coenzyme Q10 and vitamin E status in postmenopausal women.

BACKGROUND: Nitrogen-bisphosphonates (N-BPs) are the most widely used drugs for bone fragility disorders. Long-term or high-dose N-BP use is associated with unusual serious side effects such as osteonecrosis of the jaw, musculoskeletal pain, and atypical fractures of long bones. It has escaped notice that the pathway N-BPs block is central for the endogenous synthesis of coenzyme Q10, an integral enzyme of the mitochondrial respiratory chain and an important lipid-soluble antioxidant. Our objective was to assess the coenzyme Q10 and antioxidant status in relation to N-BP exposure in women with postmenopausal osteoporosis. METHODS: Seventy-one postmenopausal women (age, 73.5 ± 5.5 y) with osteoporosis and no other malignancy were included in this cross-sectional study. Seventeen were treatment naive, 27 were on oral N-BP, and 27 were on i.v. N-BP. RESULTS: Vitamin E γ-tocopherol levels (µmol/mL) were significantly reduced in N-BP users [oral, H(2) = 18.5, P = .02; i.v., H(2) = 25.2, P < .001; mean rank comparisons after Kruskal-Wallis test). Length of time (days) of N-BP exposure, but not age, was inversely associated with the coenzyme Q10/cholesterol ratio (µmol/mol) (ß = -0.27; P = .025), which was particularly low for those on i.v. N-BP (mean difference = -35.0 ± 16.9; 95% confidence interval, -65.2 to -4.9; P = .02). CONCLUSION: The degree of N-BP exposure appears related to compromised coenzyme Q10 status and vitamin E γ-tocopherol levels in postmenopausal women with osteoporosis. This phenomenon may link to certain adverse N-BP-associated effects. Confirmation of this would suggest that therapeutic supplementation could prevent or reverse certain complications of long-term N-BP therapy for at-risk individuals.

Fisetin enhances behavioral performances and attenuates reactive gliosis and inflammation during aluminum chloride-induced neurotoxicity.

Aluminum (Al) is an environmental neurotoxin that affects cerebral functions and causes health complications. However, the role of Al in arbitrating glia homeostasis and pathophysiology remains obscure. Astrocyte, microglia activation (reactive gliosis), and associated inflammatory events play a decisive role in neurodegeneration and may represent a target for treating neurodegenerative disorders. In this study, we have analyzed the role of aluminum chloride (AlCl3) in causing reactive gliosis in the brain of mice and the ability of fisetin, a flavonoid to attenuate reactive gliosis and neuronal inflammation. Reports suggest that fisetin exerts antioxidant and anti-inflammatory actions. Fisetin at a dose of 15 mg/kg body weight was orally administered, daily (pre-treated for 4 weeks before AlCl3 induction and co-treated until experimental period of 8 weeks) to mice induced with AlCl3 (200 mg/kg b.wt./day/8 weeks, orally). Administration of AlCl3 developed behavioral deficits, triggered lipid peroxidation (LPO), compromised acetylcholine esterase (AChE) activity, and reduced the levels of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and reduced glutathione (GSH), and caused histologic aberrations. These effects were accompanied by increased expressions of Glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1. Pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1ß, inducible nitric oxide synthase, were increased upon AlCl3 administration. AlCl3-induced alterations in the activities of SOD, CAT, GST, AChE and levels of GSH, LPO, activity of AChE, behavioral deficits, histologic aberrations, reactive gliosis, and inflammatory niche were attenuated on treatment with fisetin. Collectively, our results indicate that fisetin exerts neuroprotection against AlCl3-induced brain pathology.

Toxicological effects of a mixture used in weight loss products: p-synephrine associated with ephedrine, salicin, and caffeine.

p-Synephrine is an adrenergic amine found in Citrus aurantium L. fruits and has been used for weight loss in dietary supplements. There are commercial products containing this substance associated to caffeine, salicin, and ephedrine. The aim of this study was to evaluate the acute toxicity of this mixture in mice of both sexes. The significative results observed after acute oral administration to male and female mice of 300, 350, and 400 mg/kg total of p-synephrine, ephedrine, salicin, plus caffeine in a 10:4:6:80 w/w ratio included a reduction in locomotor activity and ptosis in all treated groups for both sexes. Seizures were also observed in male (400 mg/kg) and female groups (350 and 400 mg/kg). Gasping and tearing were observed in males. Salivation (400 mg/kg), agitation (350 and 400 mg/kg), and piloerection (all treated groups) were significantly observed only in females. Deaths occurred in males at 350 and 400 mg/kg treated groups and the necropsy showed cardiopulmonary hemorrhage. A reduction in locomotor activity was confirmed through the spontaneous locomotor activity test, in which the number of crossings considerably decreased (P < .01) in all treated groups. The rotarod test showed a decrease in motor coordination at 400 mg/kg. Body temperature decreased significantly (P < .01) in all treated groups compared to controls. The results suggested clear signs of toxicity of p-synephrine, ephedrine, salicin, and caffeine association; this toxicity augments the attentiveness on commercial products containing this mixture, given the expressive number of adverse events related to its utilization.

Neuroprotective effect of kaempferol against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease.

In the present study, we investigated the neuroprotective effects of kaempferol in the mouse model of Parkinson's disease, which was induced by neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We confirmed that MPTP led to behavioral deficits, depletion of dopamine and its metabolites, reduction in superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity, and the elevation of malondialdehyde (MDA) levels in the substantia nigra. When administered prior to MPTP, kaempferol improved motor coordination, raised striatal dopamine and its metabolite levels, increased SOD and GSH-PX activity, and reduced the content of MDA compared with mice treated with MPTP alone. Immunohistochemical studies using anti-tyrosine hydroxylase (TH) antibody showed that medication of kaempferol could prevent the loss of TH-positive neurons induced by MPTP. Taken together, we propose that kaempferol has shown anti-parkinsonian properties in our studies. More work is needed to explore detailed mechanisms of action.

The nicotinic acetylcholine receptor partial agonist varenicline increases the ataxic and sedative-hypnotic effects of acute ethanol administration in C57BL/6J mice.

BACKGROUND: The costs associated with alcohol abuse are staggering, therefore much effort has been put into developing new pharmacologic strategies to decrease alcohol abuse. Recently, the nicotinic acetylcholine receptor (nAChR) partial agonist varenicline has been shown to decrease ethanol consumption in both humans and animal models. METHODS: We examined the effects of varenicline on the ataxic and sedative-hypnotic effects of ethanol. First, varenicline was administered prior to placement in a locomotor activity chamber to determine whether varenicline influenced baseline locomotor activity. To determine the effect of nicotinic modulation on ethanol-induced motor incoordination, varenicline was administered 30 minutes prior to an acute ethanol injection and then mice were tested on the balance beam, dowel test, or fixed-speed rotarod. To examine ethanol's sedative-hypnotic effects, varenicline was administered 30 minutes prior to 4 g/kg ethanol and the duration of loss of righting reflex (LORR) was measured. RESULTS: Varenicline markedly reduced baseline locomotor activity in C57BL/6J mice. Varenicline increased ethanol-induced ataxia when measured on the balance beam and dowel test but had no effect when measured on the fixed-speed rotarod. Pretreatment with varenicline increased the duration of LORR. CONCLUSIONS: These data provide evidence that nAChRs may be involved in the ataxic and sedative effects of ethanol. It is possible that one mechanism that could contribute to the ability of varenicline to decrease ethanol consumption may be through increasing negative behavioral effects of alcohol.

[Chronic demyelinating polyneuropathy and B6 hypervitaminosis]. / Polyneuropathie chronique démyélinisante et hypervitaminose B6.

We report a 62-year-old patient who presented with a several month history of a peripheral sensory neuropathy with ataxia that was attributed to a chronic immune demyelinating polyneuropathy but was resistant to corticosteroid therapy. Diagnostic workup finally showed a high serum level of pyridoxin related to a chronic intake of oral vitamin medication for several years. We discuss the link between the clinical and electrophysiological manifestations of the chronic polyneuropathy, based on similar reported observations in the literature. This observation highlights the possibility of important long-term deleterious effects of vitamin oral supplementations, particularly pyridoxin.

[Feed-related selenium poisoning in swine]. / Fütterungsbedingte Selen-Vergiftung beim Schwein.

The following case report describes a selenium toxicosis in a pig-fattening farm of two finisher groups. The diseased animals partly showed ataxia and paresis or intense lameness in connection with band-like ablation of the epidermis at the coronary band. Some of them suffered from alopecia. Foot-and-mouth disease and swine vesicular disease were excluded by serological tests. Dissection revealed a multifocal bilateral symmetric poliomyelomalacia. Histological changes in the claws ranged from severe cell-decay in the germinative layer to distinctive decay of the stratum corneum. Due to damage of the claw epidermis the corium was partly exposed. Feed analysis revealed 100-fold increased selenium content in the finishing premix from the feed mill and as a result 20- to 60-fold increased selenium values in feed samples from the farm-made finisher mixture. Selenium concentration in the blood of diseased animals was 4- to 10-fold higher than normal values, which confirmed the tentative diagnosis of a selenium toxicosis.

Dietary alpha-tocopherol and neuromuscular health: search for optimal dose and molecular mechanisms continues!

Rodents fed alpha-tocopherol (alphaT)-depleted diets develop neuromuscular deficits. Unequivocal role of alphaT in the prevention of these deficits is confounded by possible neurotoxic oxidant products generated, ex vivo in alphaT-depleted diets. The discovery that large doses of alphaT could ameliorate neuromuscular deficits, attributed to very low serum alphaT caused by mutations in either the microsomal triglyceride transfer protein or the alphaT-transfer protein (alphaTTP), underscores the necessity of alphaT for neuromuscular health in humans. The discovery of human alphaTTP provided physiological relevance to biochemical data from rodents documenting alphaT-binding transfer protein, expressed exclusively in liver. The cloning of alphaTTP gene and the creation of alphaTTP-knockout mice allowed to achieve severe systemic alphaT deficiency in brain and muscles, possibly at birth, eliminating the possible confounding effects of ex vivo-generated oxidant products in vitamin E-stripped diets. alphaTTP-knockout mice have proven useful models to discover alphaT-regulated phenotypes and molecular actions of alphaT in vivo. The results suggest that antioxidant and non-antioxidant actions of alphaT in vivo may not be mutually exclusive. These studies also suggest that low levels of dietary alphaT can achieve in excess of nanomolar alphaT levels in tissues and maintain normal neuromuscular functions. This is consistent with biochemical and crystallographic data of alpha-TTP and of other alphaT-binding proteins that have dissociation constants in nanomolar range. Molecular mechanisms that cause a long delay for the development of deficiency symptoms remain enigmatic. It is likely that alphaT is metabolically stable in post-mitotic neurons and myocytes and, if it undergoes redox-cycling in vivo, a large repertoire of alphaT-regenerating systems maintains its biological activity before it is totally depleted.