Methods of increasing tonic inhibition and treating secondary insomnia

Abstract

Methods of increasing tonic inhibition in a subject in need thereof, for example a subject with Fragile X syndrome or Angelman syndrome are disclosed. Methods of treating secondary insomnia in a subject with a neurodegenerative disease or disorder are also disclosed. The methods can include administering the subject an effective amount of 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a derivative thereof, or a pharmaceutically acceptable salt thereof, increase tonic inhibition in neurons of the subject; to increase slow wave sleep (SWS) and/or slow wave activity (SWA), normalize sleep architecture, reduce secondary insomnia, increase non-rapid eye movement (NREM) sleep, increase sleep continuity, enhance delta activity within NREM, increase or improve total sleep time (TST), increase or improve sleep efficiency, reduce total time awake (TAA), reduce number of awakenings (NWA), reduce latency to persistent sleep (LPS), or to reduce wake after sleep onset (WASO), in the subject, or any combination thereof.

I claim: 
     
         1 . A method of increasing tonic inhibition of neurons comprising administering to a human subject with a neurodegenerative disease, a neurogenetic disorder, or a central nervous system disorder a pharmaceutical composition comprising an effective amount of 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a derivative thereof and a pharmaceutically acceptable carrier or excipient to increase tonic inhibition of neurons of the subject. 
     
     
         2 . The method of  claim 1 , wherein the subject has Fragile X syndrome or Fragile X-associated tremor/ataxia syndrome. 
     
     
         3 . The method of  claim 1 , wherein the subject has Angelman syndrome. 
     
     
         4 . The method of any of  claim 1 , wherein the amount of the THIP or derivative thereof is not effective to have an adverse effect in the subject. 
     
     
         5 . The method of  claim 1 , wherein the subject has secondary insomnia and the pharmaceutical composition is administered in an effective amount to increase slow wave sleep (SWS) and/or slow wave activity (SWA), normalize sleep architecture, reduce secondary insomnia, increase non-rapid eye movement (NREM) sleep, increase sleep continuity, enhance delta activity within NREM, increase or improve total sleep time (TST), increase or improve sleep efficiency, reduce total time awake (TAA), reduce number of awakenings (NWA), reduce latency to persistent sleep (LPS), reduce wake after sleep onset (WASO), or any combination thereof in the subject. 
     
     
         6 . The method of  claim 1 , wherein the neurodegenerative disease is selected from the group consisting of Parkinson's Disease (PD) and PD-related disorders, Alzheimer's Disease (AD) and other dementias, Prion Diseases such as Creutzfeldt-Jakob Disease, Corticobasal Degeneration, Frontotemporal Dementia, HIV-Related Cognitive Impairment, Mild Cognitive Impairment, Motor Neuron Diseases (MND), Spinocerebellar Ataxia (SCA), Spinal Muscular Atrophy (SMA), Friedreich's Ataxia, Lewy Body Disease, Alpers' Disease, Batten Disease, Cerebro-Oculo-Facio-Skeletal Syndrome, Corticobasal Degeneration, Gerstmann-Straussler-Scheinker Disease, Kuru, Leigh's Disease, Monomelic Amyotrophy, Multiple System Atrophy, Multiple System Atrophy With Orthostatic Hypotension (Shy-Drager Syndrome), Multiple Sclerosis (MS), Neurodegeneration with Brain Iron Accumulation, Opsoclonus Myoclonus, Posterior Cortical Atrophy, Primary Progressive Aphasia, Progressive Supranuclear Palsy, Vascular Dementia, Progressive Multifocal Leukoencephalopathy, Dementia with Lewy Bodies, Lacunar syndromes, Hydrocephalus, Wernicke-Korsakoff's syndrome, post-encephalitic dementia, cancer and chemotherapy-associated cognitive impairment and dementia, and depression-induced dementia and pseudodementia. 
     
     
         7 . The method of  claim 6 , wherein the neurodegenerative disease is Huntington's disease. 
     
     
         8 . The method of  claim 6 , wherein the neurodegenerative disease is Parkinson's disease. 
     
     
         9 . The method of  claim 6 , wherein the neurodegenerative disease is Amyotrophic lateral sclerosis. 
     
     
         10 . The method of  claim 6 , wherein the neurodegenerative disease is Alzheimer's disease. 
     
     
         11 . The method of  claim 1 , wherein the subject has not been clinically diagnosed with the neurodegenerative disease. 
     
     
         12 . The method of  claim 1 , wherein the subject has no significant physical symptoms of the neurodegenerative disease, or the clinical symptoms are too mild for an affirmative diagnosis of the neurodegenerative disease. 
     
     
         13 . The method of  claim 1 , wherein the subject has been clinically diagnosed with the neurodegenerative disease. 
     
     
         14 . The method of  claim 1 , wherein the THIP or derivative thereof is THIP or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 1 , wherein the THIP or derivative thereof is the singular active agent in the pharmaceutical composition. 
     
     
         16 . The method of  claim 1 , wherein the pharmaceutical composition is formulated for extended release. 
     
     
         17 . The method  claim 1 , wherein the pharmaceutical composition is administered once every 24-48 hours. 
     
     
         18 . The method of  claim 1 , wherein the pharmaceutical composition is administered transdermally. 
     
     
         19 . The method of  claim 18 , wherein the pharmaceutical composition is administered by contacting a transdermal patch comprising the pharmaceutical composition with the skin of the subject. 
     
     
         20 . The method of  claim 1 , wherein the pharmaceutical composition is administered to the subject in the morning or the evening. 
     
     
         21 . The method of  claim 1 , wherein the daily dosage of the THIP or derivative thereof is between about 1 mg and 20 mg. 
     
     
         22 . The method of  claim 1 , wherein the composition is administered to the subject intravenously. 
     
     
         23 . The method of  claim 22 , wherein the subject is administered a daily dosage of the THIP or derivative thereof is between about 0.001 mg and 30 mg. 
     
     
         24 . The method of  claim 23 , wherein the THIP or derivative thereof is administered at a rate of 0.001 mg/kg per hour to 1 mg/kg per hour. 
     
     
         25 . A method of treating or preventing Fragile X syndrome or Fragile X-associated tremor/ataxia syndrome in a subject comprising administering to a subject with Fragile X syndrome or Fragile X-associated tremor/ataxia syndrome a pharmaceutical composition comprising an effective amount of 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a derivative thereof and a pharmaceutically acceptable carrier or excipient to increase tonic inhibition of neurons in the subject. 
     
     
         26 . A method of treating or preventing Angelman syndrome in a subject comprising administering to a subject with Angelman syndrome a pharmaceutical composition comprising an effective amount of 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a derivative thereof and a pharmaceutically acceptable carrier or excipient to increase tonic inhibition of neurons in the subject.