topiramate and Neurodegenerative-Diseases

Extending from the triple wave epidemic of opioid-related overdose deaths, a fourth wave of high mortality involving methamphetamine and cocaine use has been gathering force. This article provides a review of the published literature on stimulants including epidemiology, pharmacology, neurobiology, medical and psychiatric consequences, withdrawal management, and medical and behavioral treatments.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adult; Anticonvulsants; Behavior Therapy; Bupropion; Central Nervous System Stimulants; Cocaine-Related Disorders; Cognitive Dysfunction; Comorbidity; Dopamine Uptake Inhibitors; Female; Humans; Illicit Drugs; Male; Mental Disorders; Methamphetamine; Mirtazapine; Neurobiology; Neurodegenerative Diseases; Opiate Overdose; Substance Withdrawal Syndrome; Topiramate; Transgender Persons; United States

A 42-year-old female patient with epilepsy and a co-morbid migraine suffered from the severe cognitive side effects of topiramate (TPM) for more than 16 years with detrimental consequences for her daily functioning, career, and social interaction. Even a prodromal stage of dementia was suggested, giving rise to fears of developing a neurodegenerative disease. Recently, cognitive monitoring of attention and executive function before and after withdrawal of TPM revealed a significant recovery from the severe negative cognitive side effects of the long-standing and inefficacious antiseizure medication (ASM). Whereas the side effects were reversible after cessation, their consequences for the patient`s biography were permanent. A considerable increase in quality of life, however, was observed without TPM and family members were impressed by the improvements. This case illustrates the potentially severe consequences of negative cognitive side effects which affect daily functioning, career and social life, thus underscoring the importance of being knowledgeable of the potential cognitive risks when prescribing an ASM. Because cognitive side effects may not depend solely on ASM choice and drug load, but also on individual idiosyncratic intolerances, and patients might stay on their treatment for many years, cognitive monitoring is highly recommended.

Topics: Adult; Anticonvulsants; Cognition; Female; Fructose; Humans; Neurodegenerative Diseases; Neuropsychological Tests; Quality of Life; Topiramate

Chronic abuse of methylphenidate (MPH) can cause serious neurotoxicity. The neuroprotective effects of topiramate (TPM) were approved, but its putative mechanism remains unclear. In current study the role of CREB/BDNF signaling pathway in TPM protection against methylphenidate-induced neurotoxicity in rat hippocampus was evaluated. 60 adult male rats were divided randomly into six groups. Groups received MPH (10mg/kg) only and concurrently with TPM (50mg/kg and 100mg/kg) and TPM (50 and 100mg/kg) only for 14 days. Open field test (OFT) was used to investigate motor activity. Some biomarkers of apoptotic, anti-apoptotic, oxidative, antioxidant and inflammatory factors were also measured in hippocampus. Expression of total (inactive) and phosphorylated (active) CREB and BDNF were also measured in gene and protein levels in dentate gyrus (DG) and CA1 areas of hippocampus. MPH caused significant decreases in motor activity in OFT while TPM (50 and 100mg/kg) inhibited MPH-induced decreases in motor activity. On the other hand, MPH caused remarkable increases in Bax protein level, lipid peroxidation, catalase activity, IL-1β and TNF-α levels in hippocampal tissue. MPH also caused significant decreases of superoxide dismutase, activity and also decreased CREB, in both forms, BDNF and Bcl-2 protein levels. TPM, by the mentioned doses, attenuated these effects and increased superoxide dismutase, glutathione peroxidase and glutathione reductase activities and also increased CREB, in both forms, BDNF and Bcl-2 protein levels and inhibited MPH induced increase in Bax protein level, lipid peroxidation, catalase activity, IL-1β and TNF-α levels. TPM also inhibited MPH induced decreases in cell number and changes in cell shapes in DG and CA1 areas. TPM can probably act as a neuroprotective agent against MPH induced neurotoxicity and this might have been mediated by CREB/BDNF signaling pathway.

Topics: Animals; Apoptosis; Brain-Derived Neurotrophic Factor; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Dose-Response Relationship, Drug; Fructose; Hippocampus; Male; Methylphenidate; Motor Activity; Neurodegenerative Diseases; Neuroprotective Agents; Oxidative Stress; Random Allocation; Rats, Wistar; Signal Transduction; Topiramate

A 46-year-old man inhaled combustible smoke of unknown chemical composition for 15-20 min in an automobile body shop. Within 1 month, he noted headache, sadness, anergia, anhedonia, agitation, poor sleep and impairment of concentration, attention and learning skills. Three years later, mental status examination showed major depression and cognitive disorder manifested by apprehension, continuous sadness, agitation, exhaustion, difficulty with word finding, bradyphrenia, short-term and long-term memory impairment, and judgement impaired by impulsive and affect-laden reactions without reflection. Impairments were noted on neuropsychiatric tests, and positron emission tomography (PET) scan of the brain with (18)F-fluorodeoxyglucose showed globally decreased and heterogeneous metabolic activity in the entire brain. Treatment included sertraline, methylphenidate, valproic acid and topiramate. At 14 years after smoke inhalation injury, he had persistent cognitive impairment. Repeat brain PET scan showed areas of improvement and deterioration. This case shows long-term brain and psychiatric dysfunction resulting after toxic smoke inhalation, with some areas of the brain having progressive deterioration between years 3 and 14 after smoke inhalation.

Topics: Activities of Daily Living; Brain; Cognition Disorders; Depressive Disorder, Major; DNA Damage; Fluorodeoxyglucose F18; Fructose; Humans; Male; Memory, Long-Term; Methylphenidate; Middle Aged; Neurodegenerative Diseases; Neuropsychological Tests; Oxidative Stress; Positron-Emission Tomography; Radiopharmaceuticals; Sertraline; Smoke Inhalation Injury; Time Factors; Topiramate; Valproic Acid

The neuroprotective properties of topiramate were evaluated in a rat model of stroke in which neurodegeneration was induced by temporary global ischemia. In this model, the ischemia resulted from 11 min of cardiac arrest during atraumatic chest compression. Resuscitated rats exhibit a characteristic neurological syndrome characterized by sound-induced convulsions, specific motor and behavioral deficits, and death of hippocampal CA1 pyramidal neurons. Topiramate, when administered i.v. 30 min after resuscitation, reduced the degree of motor impairment (P< 0.05 vs control at doses of 10 and 20 mg/kg) and seizure severity (P< 0.05 vs control at a dose of 10 mg/kg on the fifth recovery day). The highest dose of topiramate (20 mg/kg i.v.) eliminated nearly all histologic signs of hippocampal ischemic neuronal injury (P< 0.001). Phenytoin at 20 mg/kg i.v. exhibited neuroprotectant effects similar to those observed for topiramate at 20 mg/kg i.v.. In normal rats, neither topiramate nor phenytoin at 20 mg/kg i.v. induced any apparent neurological impairment; however, at 40 and 60 mg/kg i.v. both induced a mild impairment typical of most anticonvulsants. The results of this study support the concept that topiramate possesses neuroprotective properties.

Topics: Animals; Disease Models, Animal; Fructose; Ischemia; Male; Neurodegenerative Diseases; Neuroprotective Agents; Rats; Rats, Long-Evans; Topiramate