Cyclic glycyl-2-allyl proline improves cognitive performance in impaired animals

Abstract

Embodiments of this invention provide methods for therapeutic use of cyclic G-2-Allyl Proline to treat symptoms of cognitive impairment associated with developmental disorders as well as manufacture of medicaments including tablets, capsules, injectable solutions that are useful for treatment of such conditions.

What is claimed is: 
     
         1 . A method for treating a symptom of cognitive impairment in a mammal in need thereof, comprising: administering a pharmaceutically effective amount of cyclic Glycyl-2-Allyl Proline (cG-2-AllylP) to said mammal, said cognitive impairment resulting from a developmental disorder. 
     
     
         2 . The method of  claim 1 , said cG-2-AllylP comprises an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers or adjuvants. 
     
     
         3 . The method of  claim 1 , further comprising one or more excipients, carriers, additives, adjuvants or binders in a tablet or capsule. 
     
     
         4 . The method of  claim 1 , said cyclic G-2-AllylP is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracisternal, topical, infusion, implant, aerosol, inhalation, scarification, intraperitoneal, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal or vaginal. 
     
     
         5 . The method of  claim 1 , said effective amount has a lower limit of about 0.001 milligrams per kilogram mass (mg/kg) of the animal and an upper limit of about 100 mg/kg. 
     
     
         6 . The method of  claim 1 , said cognitive impairment is associated with Autism Spectrum Disorder (ASD), or Neurodevelopmental Disorder (NDD), or Down's Syndrome. 
     
     
         7 . The method of  claim 6 , said cognitive impairment is associated with Autistic Disorder, Asperger Syndrome, Childhood Disintegrative Disorder and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), and Pathological Demand Avoidance (PDA). 
     
     
         8 . The method of  claim 6 , said cognitive impairment is associated with Fragile X Syndrome (FXS), Angelman Syndrome, Tuberous Sclerosis Complex, Phelan McDermid Syndrome, Rett Syndrome, CDKL5 mutations, and X-Linked Infantile Spasm Disorder. 
     
     
         9 . The method of  claim 1 , said symptom being cognitive impairment or cognitive dysfunction, one or more signs or symptoms of memory loss, loss of spatial orientation, decreased ability to learn, decreased ability to form short- or long-term memory, decreased episodic memory, decreased ability to consolidate memory, decreased spatial memory, decreased synaptogenesis, decreased synaptic stability, deficits in executive function, deficits in cognitive mapping and scene memory, deficits in declarative and relational memory, decreased rapid acquisition of configural or conjunctive associations, decreased context-specific encoding and retrieval of specific events, decreased episodic and/or episodic-like memory, anxiety, abnormal fear conditioning, abnormal social behaviour, repetitive behaviour, abnormal nocturnal behavior, seizure activity, abnormal locomotion, abnormal expression of Phospho-ERK1/2 and Phospho-Akt, and bradycardia 
     
     
         10 . The method of  claim 1 , said treatment producing an improvement in a symptom of ASD or NDD as assessed using one or more clinical tests selected from the group consisting of The Rett Syndrome Natural History/Clinical Severity Scale, Aberrant Behavior Checklist Community Edition (ABC), Vineland Adaptive Behavior Scales, Clinical Global Impression of Severity (CGI-S), Clinical Global Impression Improvement (CGI-I), the Caregiver Strain Questionnaire (CSQ), or one or more physiological tests selected from the group consisting of electroencephalogram (EEG) spike frequency, overall power in frequency bands of an EEG, hemispheric coherence of EEG frequencies, stereotypic hand movement, QTc and heart rate variability (HRV), respiratory irregularities and coupling of cardiac and respiratory function compared to control animals not suffering from said disorder. 
     
     
         11 . The method of  claim 1 , said cognitive impairment is caused by a decrease in glutamate receptors in the granular cell layer (CA1) of the hippocampus of said mammal. 
     
     
         12 . The method of  claim 1 , said cG-2-AllylP causes an increase in AMPA receptors in the granular cell layer (CA1) of the hippocampus of said mammal. 
     
     
         13 . The method of  claim 1 , said cG-2-AllylP causes an increase in neuronal plasticity caused by said cG-2AllylP in the granule cell layer (CA1) and the pyramidal cell layer (CA3) regions of said mammal's hippocampus. 
     
     
         14 . The method of  claim 1 , said cG-2-AllylP causes an increase in spatial memory in said mammal. 
     
     
         15 . The method of  claim 1 , said cG-2-AllylP causes in increase in novelty recognition in said mammal. 
     
     
         16 . The method of  claim 1 , said cG-2-AllylP improves glutaminergic neurotransmission in the hippocampus of said mammal. 
     
     
         17 . The method of  claim 1 , said cG-2-AllylP causes an increase in the number of pre-synaptic vesicles in the CA1 and C3 regions of said mammal's hippocampus. 
     
     
         18 . The method of  claim 1 , said cG-2-AllylP causes an increase in synaptic density in the hippocampus of said mammal.