Kirk Nylen
University of Toronto
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Featured researches published by Kirk Nylen.
Experimental Neurology | 2008
Kirk Nylen; Jose Luis Perez Velazquez; Sergei S. Likhodii; Miguel A. Cortez; Lily Shen; Yevgen Leshchenko; Khosrow Adeli; K. Michael Gibson; W.M. Burnham; O. Carter Snead
Succinic semialdehyde dehydrogenase (SSADH) deficiency is a heritable disorder of GABA degradation characterized by ataxia, psychomotor retardation and seizures. To date, there is no effective treatment for SSADH deficiency. We tested the hypothesis that a ketogenic diet (KD) would improve outcome in an animal model of SSADH deficiency, the SSADH knockout mouse (Aldh5a1-/-). Using a 4:1 ratio of fat to combined carbohydrate and protein KD we set out to compare the general phenotype, in vivo and in vitro electrophysiology and [35S]TBPS binding in both Aldh5a1-/- mice and control (Aldh5a1+/+) mice. We found that the KD prolonged the lifespan of mutant mice by >300% with normalization of ataxia, weight gain and EEG compared to mutants fed a control diet. Aldh5a1-/- mice showed significantly reduced mIPSC frequency in CA1 hippocampal neurons as well as significantly decreased [35S]TBPS binding in all brain areas examined. In KD fed mutants, mIPSC activity normalized and [35S]TBPS binding was restored in the cortex and hippocampus. The KD appears to reverse toward normal the perturbations seen in Aldh5a1-/- mice. Our data suggest that the KD may work in this model by restoring GABAergic inhibition. These data demonstrate a successful experimental treatment for murine SSADH deficiency using a KD, giving promise to the idea that the KD may be successful in the clinical treatment of SSADH deficiency.
Biochimica et Biophysica Acta | 2009
Kirk Nylen; Jose Luis Perez Velazquez; Venus Sayed; K. Michael Gibson; W.M. Burnham; O. Carter Snead
BACKGROUND Succinic semialdehyde dehydrogenase (SSADH) deficiency is an inborn error of GABA metabolism characterized clinically by ataxia, psychomotor retardation and seizures. A mouse model of SSADH deficiency, the Aldh5a1(-/-) mouse, has been used to study the pathophysiology and treatment of this disorder. Recent work from our group has shown that the ketogenic diet (KD) is effective in normalizing the Aldh5a1(-/-) phenotype, although the mechanism of the effect remains unclear. METHODS Here, we examine the effects of a KD on the number of hippocampal mitochondria as well as on ATP levels in hippocampus. Electron microscopy was performed to determine the number of mitochondria in the hippocampus of Aldh5a1(-/-) mice. Adenosine triphosphate (ATP) levels were measured in hippocampal extracts. RESULTS Our results show that the KD increases the number of mitochondria in Aldh5a1(-/-) mice. We also show that Aldh5a1(-/-) mice have significant reductions in hippocampal ATP levels as compared to controls, and that the KD restores ATP in mutant mice to normal levels. GENERAL SIGNIFICANCE Taken together, our data suggest that the KDs actions on brain mitochondria may play a role in the diets ability to treat murine SSADH deficiency.
Neurotherapeutics | 2009
Kirk Nylen; Sergei S. Likhodii; W. McIntyre Burnham
SummaryThe ketogenic diet is a high-fat, low-carbohydrate diet used to treat drug-resistant seizures, especially in children. A number of possible mechanisms of action have been proposed to explain the anticonvulsant effects of the diet. Four of these hypothetical mechanisms are discussed in the present article: the pH hypothesis, the metabolic hypotheses, the amino acid hypothesis, and the ketone hypothesis.
Epilepsia | 2005
Kirk Nylen; Sergei S. Likhodii; Peter A. Abdelmalik; Jasper Clarke; W. McIntyre Burnham
Summary: Purpose: The pentylenetetrazol (PTZ) infusion test was used to compare seizure thresholds in adult and young rats fed either a 4:1 ketogenic diet (KD) or a 6.3:1 KD. We hypothesized that both KDs would significantly elevate seizure thresholds and that the 4:1 KD would serve as a better model of the KD used clinically.
Epilepsy Research | 2006
Ameer Y. Taha; Bogdan M. Baghiu; Richard Lui; Kirk Nylen; David W.L. Ma; W. McIntyre Burnham
BACKGROUND Polyunsaturated fatty acids have been reported to increase seizure threshold and to reduce seizure duration and severity in rats. OBJECTIVE The purpose of the present study was to test the anticonvulsant effects of an essential fatty acid mixture containing linoleic and alpha-linolenic acids at a 4:1 ratio (SR-3 compound), using the pentylenetetrazol seizure model in Long-Evans hooded rats. RESULTS There were no significant effects of SR-3 on seizure latency, duration or severity (P>0.05). There were also no significant differences in the incidence of myoclonic jerks, forelimb and hindlimb clonus, forelimb and hindlimb tonus or running fits in rats that received SR-3, as compared to control rats (P>0.05). CONCLUSION Linoleic and alpha-linolenic polyunsaturated fatty acids have no beneficial effects on seizure latency, duration, average severity or incidence.
Brain Research | 2006
Deborah Lonsdale; Kirk Nylen; W. McIntyre Burnham
Progesterone is a neurosteroid that modulates neuronal excitability. The anticonvulsant effects of progesterone are largely mediated by the actions of its metabolites. The purpose of this study was to measure the anticonvulsant effects of progesterone, 5alpha-dihydroprogesterone, and allopregnanolone against amygdala-kindled seizures in male rats. The amygdala kindling model is a model of human complex partial seizures with secondary generalization. A bipolar electrode was chronically implanted in the right amygdala of male Wistar rats. All subjects were kindled to 30 stage 5 seizures and stability tested. Multiple doses of progesterone, 5alpha-dihydroprogesterone, or allopregnanolone were administered in separate dose-response studies. The antiseizure effects of each compound were determined. A progesterone time-response study was also conducted. At 30 min after injection, progesterone had an ED50 of 65.3 mg/kg against the secondarily generalized seizure and an ED50 of 114 mg/kg against the focal seizure. 5alpha-dihydroprogesterone had a low ED50 of 6.2 mg/kg against both the generalized component of the amygdala-kindled seizure and the focal seizure. Allopregnanolone had an ED50 of 15.2 mg/kg against the secondarily generalized seizure and was not effective against the focal seizure. Progesterone is an effective anticonvulsant against the secondarily generalized component of amygdala-kindled seizures in male rats. Progesterone is only effective against the focal seizure at high ataxic doses. 5alpha-dihydroprogesterone is a potent anticonvulsant against both the kindled amygdala focal discharge and the secondarily generalized seizure. Allopregnanolone is an effective anticonvulsant against the secondarily generalized component of the seizure, but not against the amygdala focal discharge.
Epilepsia | 2008
Sergei S. Likhodii; Kirk Nylen; W. McIntyre Burnham
Recent interest in the anticonvulsant effects of acetone has stemmed from studies related to the ketogenic diet (KD). The KD, a high‐fat diet used to treat drug‐resistant seizures, raises blood and brain levels of three ketones: beta‐hydroxybutyrate, acetoacetate, and acetone. An obvious question is whether these ketones have anticonvulsant properties. We found that neither beta‐hydroxybutyrate nor acetoacetate has proven to be anticonvulsant. Acetone, however, is clearly anticonvulsant at physiological, and near‐physiological, nontoxic concentrations. Despite knowledge of acetones anticonvulsant properties since the 1930s, acetone had never been characterized using the standard animal seizure tests. In our recent experiments, acetone was found to be active in animal models of tonic–clonic seizures, typical absence seizures, complex partial seizures, and atypical absence seizures associated with Lennox–Gastaut syndrome. Therapeutic indices are either comparable or better than that of valproate, a standard broad‐spectrum anticonvulsant. A number of acetone‐like molecules have also been tested, and these also show good potency up to a “cutoff” point of nine carbons contained in the side chain. Above this number, potency disappears, suggesting the possibility of a receptor for acetone and its analogs.
Epilepsy & Behavior | 2008
Lee S. Stewart; Kirk Nylen; Michael A. Persinger; Miguel A. Cortez; K. Michael Gibson; O. Carter Snead
Human succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism associated with motor impairment and epileptic seizures. Similarly, mice with targeted deletion of the Aldh5a1 gene (Aldh5a1(-/-)) exhibit SSADH deficiency and seizures early in life. These seizures begin as absence seizures the second week of life, but evolve into generalized convulsive seizures that increase in severity and become lethal during the fourth postnatal week. The seizures are alleviated and survival is prolonged when the mutant animals are weaned onto a ketogenic diet (KD). The persistence of spontaneous, recurrent, generalized tonic-clonic seizures in KD-treated adult Aldh5a1(-/-) mice allowed us to quantify their daily (circadian) distribution using a novel behavioral method based on the detection of changes in movement velocity. Adult KD-treated Aldh5a1(-/-) mice exhibited a seizure phenotype characterized by fits of wild running clonus accompanied by jumping and bouncing. These hypermotor seizures were largely spontaneous and occurred daily in a nonrandom pattern. The seizure rhythm showed a peak shortly after dark phase onset (2008 hours) with near-24-hour periodicity. Age-matched wild-type littermates showed no evidence of abnormal motor behavior. These new data suggest that generalized tonic-clonic seizures in Aldh5a1(-/-) mice are more frequent during a specific time of day and will provide useful information to clinicians for the treatment of seizures associated with human SSADH deficiency.
Clinical Neurophysiology | 2007
Kirk Nylen; Sergei Likhodii; Jose Luis Perez Velasquez; W.M. Burnham; K. Michael Gibson; O. Carter Snead
Objective: To determine the clinical, behavioral and EEG changes after traumatic brain injury (TBI) in adolescents and young adults. Rationale: Damage to the brain, especially the temporal lobes, is associated with a persistent post-concussion syndrome, borderline or sociopathic personality disorder and impulse dyscontrol. An overlap with complex partial seizures of temporal lobe origin is suggested: impaired responsiveness, olfactory hallucinations, déjà vu or jamais vu, in ictal or interictal behaviour. We hypothesize that temporal lobe damage results in impaired cognitive functions associated with personality changes and abnormal temporal EEG findings. A retrospective study of youth (16–35 years of age) after moderate TBI had detailed neurological (PAH) and neuropsychiatric (MS) evaluation independently, and an 18-channel EEG sleep studies with zygomatic electrodes. Antiepileptic therapy employed the usual AEDs appropriate for the seizure types, with monitoring of blood levels. Neuroimaging with head CT and/or MRI was performed, with attention to medial temporal structures. Follow up by an experienced team of neurologist/epileptologist (PAH) and neuropsychiatrist (MS) extended from 6 months over 6 years (mean 3 years). Data were analysed for headaches, seizure control, AEDs and side-effects, attention, behavioural disorders, structural lesions and EEG abnormalities. When available, detailed neuropsychological studies were analyzed with statistical tests of significance (P < 0.05). Preliminary results suggest clinical features following moderate TBI of temporal lobe dysfunction: verbal and non-verbal memory, learning and amnesic disorders, complex partial seizures, overlapping the borderline personality disorder. These findings suggest limbic dysfunction underlying the behavioral disturbance, EEG and structural changes in medial temporal structures after TBI.
Clinical Neurophysiology | 2008
Kirk Nylen; Sergei Likhodii; Jose Luis Perez Velasquez; W.M. Burnham; K. Michael Gibson; O. Carter Snead
Background: Juvenile myoclonic epilepsy (JME) is a common type of idiopathic generalised epilepsy and is distinctively characterized by myoclonic jerks often associated to generalised tonic-clonic seizures (GTCS) and typical absence seizures. EEG asymmetries are not uncommon in JME and can contribute to the misdiagnosis of this syndrome. The objective of this study is to further characterize patients with focal electroencephalographic abnormalities and specifically in term of response to treatment. Methods: We retrospectively revised clinical and EEG data of a group of consecutive JME patients followed at our Epilepsy Service. The first EEG available for each patient was reviewed by two independent electroencephalographers. Results: Twenty-eight patients with JME were identified: 11 (39.3%) were resistant to at least one anti-epileptic drug (AED), including valproic acid, lamotrigine, topiramate or levetiracetam. All patients except two had generalised epileptiform abnormalities. In our group, EEG asymmetries were detected in 57.1% of the cases. In the AED-resistant group, 63.6% had asymmetries versus 52.9% in the AED-sensitive group but the difference was not statistically significant. Concordance between examiners was good. Analysis of patients with and without asymmetries showed no statistically significant differences in comparisons of age, familial history of seizure, presence of polyspike and slow wave, photosensitivity and timing of EEG related to onset of treatment. Conclusion: Focal electroencephalographic abnormalities are frequent in patients with JME. These features should not be misinterpreted as being indicative of partial epilepsy. In our group, asymmetries were not associated with resistance to treatment.