Therapeutic agent composition and method of use

Abstract

The invention relates to the use of cyclic Prolyl Glycine (“cyclic PG” or “cPG”) and analogs and mimetics thereof, as neuroprotective agents for the treatment and or prevention of neurological disorders including but not limited to cerebral ischemia or cerebral infarction resulting from a range of phenomena, such as thromboembolic or hemorrhagic stroke, cerebral basospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as to the treatment and prevention of chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, and as anticonvulsants.

1 - 48 . (canceled)  
   
   
       49 . A method of treating a patient to protect neurons and glia otherwise destined to die as a result of an insult from disease or injury which comprises administering to said patient Cyclic PG (cPG) or an analog or a peptidomimetic thereof in an amount sufficient to prevent the neurons and glia from dying.  
   
   
       50 . The method according to claim  1 , wherein Cyclic PG is an anti-apoptotic agent in the central nervous system.  
   
   
       51 . The method according to claim  1 , wherein Cyclic PG is an anti-necrotic agent in the central nervous system.  
   
   
       53 . The method according to claim  1 , wherein said disease is a neurogenerative disease selected from the group consisting of Alzheimer's disease, multiple sclerosis, Huntington's disease and Parkinson's disease.  
   
   
       54 . The method according to claim  1 , wherein said injury is a neurological injury selected from the group consisting of traumatic brain injury, stroke, cardiac artery bypass graft surgery, toxins and asphyxia.  
   
   
       55 . The method of claim  1  wherein the peptide administered is cPG.  
   
   
       56 . A method of regenerating neurons and glia cell loss as a result of and insult from injury or disease, comprising the step of: 
 administering Cyclic PG (cPG), a cPG analogue, or a peptidomimetic thereof in an amount sufficient to regenerate new neurons and glia,    wherein cPG, cPG analogue, or said petidiomimetic thereof can serve as a neurogenesis agent in the central nervous system.    
   
   
       57 . The method according to  claim 56 , wherein said administration is in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier.  
   
   
       58 . The method according to  claim 56 , wherein said administration is directly to the brain or cerebrospinal fluid.  
   
   
       59 . The method according to  claim 56 , wherein said administration is in combination with artificial cerebrospinal fluid.  
   
   
       60 . The method according to  claim 56 , wherein said administration is through one or more routes selected from the group consisting of intravenous, oral, rectal, nasal, subcutaneous, inhalation, intraperitoneal, and intramuscular.  
   
   
       61 . The method according to  claim 56 , wherein said administration is combined with one or more neuroprotective agents selected from the group consisting of insulin-like growth factor-I (IGF-I), insulin growth-like factor-II (IGF-II), transforming growth factor-β 1 , activin, a growth hormone, a nerve growth factor, a growth hormone binding protein, a IGF-binding protein, basic fibroblast growth factor, acidic fibroblast growth factor, the hst/Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-induced growth factor, int-2, fibroblast growth factor homologous factor-1 (FHF-1), FHF-2, FHF-3, FHF-4, karatinocyte growth factor 2, glial-activating factor, FGF-10 and FGF-16, ciliary neurotrophic factor, brain derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial-cell line derived neurotrophic factor, activity-dependant neurotrophic factor, cytokine leukemia, inhibiting factor, oncostatin M, interleukin, β, α, χ, or consensus interferon, TNF-α, clomethiazole; kynurenic acid, Semax, FK506 (tacrolimus), L-threo-1-pheyl-2-decanoylamino-3-morpholino-1-propanol, andrenocorticotropin-(4-9_analogue (ORG 2766) and dizolcipine (MK-801)), selegiline, a glutamate antagonist (e.g. NPS1506, GV1505260, MK-801, GV150526), a AMPA antagonist (e.g. 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070 and LY300164), a anti-inflammatory agents directed against the addressin MAdCAM-1 and/or integrin α4 receptors (α4β1 and α4β7) (e.g. anti-MAdCAM-1mAb MECA-367 (ATCC accession no. HB-9478) and a combination thereof.  
   
   
       62 . The method according to  claim 56 , wherein said administration is combined with one or more anti-inflammatory agents selected from the group consisting of anti-integrin alpha 4 subunit reagents, anti-integrin beta 7 subunit reagents, anti-integrin beta 2 subunit reagents, anti-integrin alpha L subunit reagents, anti-MAdCAM-1, anti-VCAM-1 reagents, and anti-ICAM reagents.  
   
   
       63 . A method of repairing damaged neurons and glia cell loss as a result of and insult from injury or disease, comprising the step of: 
 administering cPG , cPG analogue, or a peptidomimetic thereof in an amount sufficient to regenerate new neurons and glia,    wherein cPG, cPG analogue, or a petidiomimetic thereof can serve as a neurorescue agent in the central nervous system.    
   
   
       64 . The method according to  claim 63 , wherein the dosage range of cPG, cPG analogue, or a peptidomimetic thereof if from about 1 μg to about 100 mg per kg of body weight.  
   
   
       65 . The method according to  claim 63 , wherein said administration is in the form of a pharmaceutical composition including pharmaceutically acceptable carrier thereof.  
   
   
       66 . The method according to  claim 63 , wherein said administration is in combination with artificial cerebrospinal fluid.  
   
   
       67 . The method according to  claim 63 , wherein said administration is combined with one or more neuroprotective agents selected from the group consisting of insulin-like growth factor-I (IGF-I), insulin growth-like factor-II (IGF-fl), transforming growth factor-β1, activin, a growth hormone, a nerve growth factor, a growth hormone binding protein, a IGF-binding protein, basic fibroblast growth factor, acidic fibroblast growth factor, the hst/Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-induced growth factor, int-2, fibroblast growth factor homologous factor-1 (FHF-1), FHF-2, FHF-3, FHF-4, karatinocyte growth factor 2, glial-activating factor, FGF-10 and FGF-16, ciliary neurotrophic factor, brain derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial-cell line derived neurotrophic factor; activity-dependant neurotrophic factor, cytokine leukemia, inhibiting factor, oncostatin M, interleukin, β, α, χ, or consensus interferon, TNF-α, clomethiazole; kynurenic acid, Semax, FK506 (tacrolimus), L-threo-1-pheyl-2-decanoylamino-3-morpholino-1-propanol, andrenocorticotropin-(4-9_analogue (ORG 2766) and dizolcipine (MK-801)), selegiline, a glutamate antagonist (e.g. NPS1506, GV1505260, MK-801, GV150526), a AMPA antagonist (e.g. 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070 and LY300164), a anti-inflammatory agents directed against the addressin MAdCAM-1 and/or integrin α4 receptors (α4,β1 and α4β7) (e.g. anti-MAdCAM-1mAb MECA-367 (ATCC accession no. HB-9478) and a combination thereof.  
   
   
       68 . The method of  claim 63 , wherein said administration is combined with one or more anti-inflammatory agents selected from the group consisting of anti-integrin alpha 4 subunit reagents, anti-integrin beta 7 subunit reagents, anti-integrin beta 2 subunit reagents, anti-integrin alpha L subunit reagents, anti-MAdCAM-1, anti-VCAM-1 reagents, and anti-ICAM reagents.