Compositions for restoring gene expression in neuropsychiatric or neurodegenerative disorders

Abstract

Methods for increasing reelin (RELN) levels in the brain of a subject in need thereof, as well as compositions for use in such methods, are provided. In addition, methods and compositions are described herein which may be used in the treatment of neuropsychiatric or neurodegenerative disorders, such as schizophrenia and Alzheimer's disease (AD). Compositions described herein may comprise whey protein isolate and/or whey protein concentrate, a source of the glutathione precursor cysteine. The provided methods and compositions are not limited to increasing RELN levels, and may be used to correct a number of other neurological disregulations or abnormalities occurring in a subject in need thereof.

What is claimed is: 
     
         1 . A method for increasing reelin (RELN) levels in the brain of a subject in need thereof, said method comprising:
 administering a composition comprising whey protein isolate and/or whey protein concentrate to the subject.   
     
     
         2 . The method of  claim 1 , further comprising a step of:
 measuring an initial RELN level of the subject and comparing the measured initial RELN level to a healthy RELN level,   wherein the subject is identified as having a reduced RELN level in need of increase when the measured initial RELN level is less than the healthy RELN level.   
     
     
         3 . The method of  claim 1  or  2 , wherein the subject in need thereof suffers from a neuropsychiatric or neurodegenerative disorder. 
     
     
         4 . The method of  claim 3 , wherein the subject in need thereof suffers from schizophrenia. 
     
     
         5 . The method of  claim 3 , wherein the subject in need thereof suffers from Alzheimer's disease (AD). 
     
     
         6 . The method of  claim 3 , wherein the subject in need thereof suffers from a neurological disorder characterized by enhanced expression of heme oxygenase-1 and/or increased oxidative stress in brain such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, amyotrophic lateral sclerosis, other motor neuron disorders, Down's syndrome, Creutzfeldt-Jakob disease, other prion diseases, multiple sclerosis, cerebral ischemia, cerebral hemorrhage, traumatic brain injury, spinal cord injury, cerebral malaria, schizophrenia, bipolar disease with psychosis, or autism. 
     
     
         7 . A method for treating, preventing, or ameliorating symptoms of a neuropsychiatric disease or a neurodegenerative disorder in a subject in need thereof, said method comprising:
 administering a composition comprising whey protein isolate and/or whey protein concentrate to the subject.   
     
     
         8 . The method according to  claim 7 , wherein the composition comprising whey protein isolate and/or whey protein concentrate is administered to increase reelin (RELN) levels in the subject. 
     
     
         9 . The method of  claim 8 , further comprising a step of:
 measuring an initial RELN level of the subject and comparing the measured initial RELN level to a healthy RELN level,   wherein the subject is identified as being particularly susceptible to treatment when the measured initial RELN level is less than the healthy RELN level.   
     
     
         10 . The method of any one of  claims 7 - 9 , wherein the neuropsychiatric disease or neurodegenerative disorder is schizophrenia. 
     
     
         11 . The method of any one of  claims 7 - 9 , wherein the neuropsychiatric disease or neurodegenerative disorder is Alzheimer's disease (AD). 
     
     
         12 . The method of any one of  claims 7 - 9 , wherein the neuropsychiatric disease or neurodegenerative disorder is a neurological disorder characterized by enhanced expression of heme oxygenase-1 and/or increased oxidative stress in brain such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, amyotrophic lateral sclerosis, other motor neuron disorders, Down's syndrome, Creutzfeldt-Jakob disease, other prion diseases, multiple sclerosis, cerebral ischemia, cerebral hemorrhage, traumatic brain injury, spinal cord injury, cerebral malaria, schizophrenia, bipolar disease with psychosis, or autism. 
     
     
         13 . Use of a composition comprising whey protein isolate and/or whey protein concentrate for increasing reelin (RELN) levels in a subject in need thereof. 
     
     
         14 . Use of a composition comprising whey protein isolate and/or whey protein concentrate in the manufacture of a medicament for increasing reelin (RELN) levels in a subject in need thereof. 
     
     
         15 . Use of a composition comprising whey protein isolate and/or whey protein concentrate for treating, preventing, or ameliorating symptoms of a neuropsychiatric disease or a neurodegenerative disorder in a subject in need thereof. 
     
     
         16 . Use of a composition comprising whey protein isolate and/or whey protein concentrate in the manufacture of a medicament for treating, preventing, or ameliorating symptoms of a neuropsychiatric disease or a neurodegenerative disorder in a subject in need thereof. 
     
     
         17 . A method for restoring serotonin levels; normalizing MnSOD mRNA levels; augmenting glutathione (GSH) levels in brain cells; augmenting whole brain GSH/glutathione disulfide (GSSG) ratios; restoring GAD67 levels; reversing reduction of Nrxn1; reversing reduction of Nlgn2; preventing HMOX1-related dysregulation of miR-128 expression; improving HMOX1-related changes in brain dopamine, dopamine metabolites, serotonin, norephinephrine, and epinephrine; restoring deficient DOPAC/DA ratios; augmenting norepinephrine and dopamine concentrations in the prefrontal cortex; and/or correcting prefrontal cortex hypodopaminergia in a subject in need thereof, said method comprising:
 administering a composition comprising whey protein isolate and/or whey protein concentrate to the subject.   
     
     
         18 . A method for augmenting GSH reserves in the brain; normalizing brain MnSOD mRNA levels; restoration of redox homeostasis; normalization of brain dopamine, serotonin, norepinephrine, and/or epinephrine levels; normalization of brain DOPAC/DA ratios; restoring GAD67 levels; reversing reduction of Nrxn1; reversing reduction of Nlgn2; preventing HMOX1-related dysregulation of miR-128 expression; and/or ameliorating hyperlocomotion and/or stereotypic behaviour; or any combination thereof; in a subject in need thereof, said method comprising:
 administering a composition comprising whey protein isolate and/or whey protein concentrate to the subject.   
     
     
         19 . The method according to  claim 17  or  18 , wherein the subject suffers from, or is a risk of developing, a neuropsychiatric or neurodegenerative disorder. 
     
     
         20 . The method according to  claim 19 , wherein the neuropsychiatric or neurodegenerative disorder is schizophrenia. 
     
     
         21 . The method according to  claim 19 , wherein the neuropsychiatric or neurodegenerative disorder is Alzheimer's disease (AD). 
     
     
         22 . The method according to  claim 19 , wherein the neuropsychiatric or neurodegenerative disorder is a neurological disorder characterized by enhanced expression of heme oxygenase-1 and/or increased oxidative stress in brain such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, amyotrophic lateral sclerosis, other motor neuron disorders, Down's syndrome, Creutzfeldt-Jakob disease, other prion diseases, multiple sclerosis, cerebral ischemia, cerebral hemorrhage, traumatic brain injury, spinal cord injury, cerebral malaria, schizophrenia, bipolar disease with psychosis, or autism. 
     
     
         23 . The method according to  claim 7 , wherein the composition comprising whey protein isolate and/or whey protein concentrate is administered for restoring serotonin levels; normalizing MnSOD mRNA levels; augmenting glutathione (GSH) levels in brain cells; augmenting whole brain GSH/glutathione disulfide (GSSG) ratios; restoring GAD67 levels; reversing reduction of Nrxn1; reversing reduction of Nlgn2; preventing HMOX1-related dysregulation of miR-128 expression; improving HMOX1-related changes in brain dopamine, dopamine metabolites, serotonin, norephinephrine, and epinephrine; restoring deficient DOPAC/DA ratios; augmenting norepinephrine and dopamine concentrations in the prefrontal cortex; and/or correcting prefrontal cortex hypodopaminergia in the subject. 
     
     
         24 . The method according to  claim 7 , wherein the composition comprising whey protein isolate and/or whey protein concentrate is administered for augmenting GSH reserves in the brain; normalizing brain MnSOD mRNA levels; restoration of redox homeostasis; normalization of brain dopamine, serotonin, norepinephrine, and/or epinephrine levels; normalization of brain DOPAC/DA ratios; restoring GAD67 levels; reversing reduction of Nrxn1; reversing reduction of Nlgn2; preventing HMOX1-related dysregulation of miR-128 expression; and/or ameliorating hyperlocomotion and/or stereotypic behaviour; or any combination thereof; in the subject. 
     
     
         25 . Use of a composition comprising whey protein isolate and/or whey protein concentrate for restoring serotonin levels; normalizing MnSOD mRNA levels; augmenting glutathione (GSH) levels in brain cells; augmenting whole brain GSH/glutathione disulfide (GSSG) ratios; restoring GAD67 levels; reversing reduction of Nrxn1; reversing reduction of Nlgn2; preventing HMOX1-related dysregulation of miR-128 expression; improving HMOX1-related changes in brain dopamine, dopamine metabolites, serotonin, norephinephrine, and epinephrine; restoring deficient DOPAC/DA ratios; augmenting norepinephrine and dopamine concentrations in the prefrontal cortex; and/or correcting prefrontal cortex hypodopaminergia in a subject in need thereof. 
     
     
         26 . Use of a composition comprising whey protein isolate and/or whey protein concentrate for augmenting GSH reserves in the brain; normalizing brain MnSOD mRNA levels; restoration of redox homeostasis; normalization of brain dopamine, serotonin, norepinephrine, and/or epinephrine levels; normalization of brain DOPAC/DA ratios; restoring GAD67 levels; reversing reduction of Nrxn1; reversing reduction of Nlgn2; preventing HMOX1-related dysregulation of miR-128 expression; and/or ameliorating hyperlocomotion and/or stereotypic behaviour; or any combination thereof; in a subject in need thereof. 
     
     
         27 . Use of a composition comprising whey protein isolate and/or whey protein concentrate in the manufacture of a medicament for restoring serotonin levels; normalizing MnSOD mRNA levels; augmenting glutathione (GSH) levels in brain cells; augmenting whole brain GSH/glutathione disulfide (GSSG) ratios; restoring GAD67 levels; reversing reduction of Nrxn1; reversing reduction of Nlgn2; preventing HMOX1-related dysregulation of miR-128 expression; improving HMOX1-related changes in brain dopamine, dopamine metabolites, serotonin, norephinephrine, and epinephrine; restoring deficient DOPAC/DA ratios; augmenting norepinephrine and dopamine concentrations in the prefrontal cortex; and/or correcting prefrontal cortex hypodopaminergia in a subject in need thereof. 
     
     
         28 . Use of a composition comprising whey protein isolate and/or whey protein concentrate in the manufacture of a medicament for augmenting GSH reserves in the brain; normalizing brain MnSOD mRNA levels; restoration of redox homeostasis; normalization of brain dopamine, serotonin, norepinephrine, and/or epinephrine levels; normalization of brain DOPAC/DA ratios; restoring GAD67 levels; reversing reduction of Nrxn1; reversing reduction of Nlgn2; preventing HMOX1-related dysregulation of miR-128 expression; and/or ameliorating hyperlocomotion and/or stereotypic behaviour; or any combination thereof; in a subject in need thereof. 
     
     
         29 . The method according to any one of  claim 1 - 6 ,  8 - 11 , or  12 , wherein the RELN levels are neuronal RELN levels. 
     
     
         30 . The use according to  claim 13  or  14 , wherein the RELN levels are neuronal RELN levels. 
     
     
         31 . The method or use according to  claim 29  or  30 , wherein the RELN levels are levels in the prefrontal cortex of the brain. 
     
     
         32 . The method or use according to any one of  claims 1 - 31 , wherein the subject is a mammal. 
     
     
         33 . The method or use according to any one of  claims 1 - 32 , wherein the subject is a human. 
     
     
         34 . A method for inducing or restoring RELN expression and/or signalling in the entorhinal cortex and/or hippocampus of a subject in need thereof, said method comprising:
 administering a composition comprising whey protein isolate and/or whey protein concentrate to the subject.   
     
     
         35 . The method according to  claim 34 , wherein the subject has or is at risk of developing schizophrenia or Alzheimer's Disease. 
     
     
         36 . Use of a composition comprising whey protein isolate and/or whey protein concentrate for inducing or restoring RELN expression and/or signalling in the entorhinal cortex and/or hippocampus of a subject in need thereof. 
     
     
         37 . Use of a composition comprising whey protein isolate and/or whey protein concentrate in the manufacture of a medicament for inducing or restoring RELN expression and/or signalling in the entorhinal cortex and/or hippocampus of a subject in need thereof. 
     
     
         38 . The use according to  claim 36  or  37 , wherein the subject has or is at risk of developing schizophrenia or Alzheimer's Disease. 
     
     
         39 . A method for treating, preventing, or ameliorating symptoms of Alzheimer's Disease in a subject in need thereof, said method comprising:
 administering a composition comprising whey protein isolate and/or whey protein concentrate to the subject.   
     
     
         40 . Use of a composition comprising whey protein isolate and/or whey protein concentrate for treating, preventing, or ameliorating symptoms of Alzheimer's Disease in a subject in need thereof. 
     
     
         41 . Use of a composition comprising whey protein isolate and/or whey protein concentrate in the manufacture of a medicament for treating, preventing, or ameliorating symptoms of Alzheimer's Disease in a subject in need thereof. 
     
     
         42 . The method or use according to any one of  claims 39 - 41 , wherein the composition is for preserving or restoring cognitive function in the subject. 
     
     
         43 . The method or use according to any one of  claims 34 - 42 , wherein the composition is administered in an amount sufficient to provide at least one of:
 an increase in RELN levels in the entorhinal cortex;   an increase in RELN levels in the dentate gyrus;   an increase in RELN levels in the CA1 region;   an increase in RELN levels in the CA3 region;   a correction in a deficit in cortical GSH levels;   a restoration of GAD67 expression in the hippocampal-entorhinal cortex sub-region;   a restoration of p-CREB levels in the hippocampal-entorhinal cortex sub-region;   an increase in RELN levels in layer II of the entorhinal cortex;   a prevention of loss of RELN positive neurons in the entorhinal cortex; or   a restoration of GAD67 expression in the dentate gyrus and/or CA3 region of the hippocampus.   
     
     
         44 . The method or use according to any one of  claims 34 - 43 , wherein the subject is a mammal. 
     
     
         45 . The method or use according to any one of  claims 34 - 44 , wherein the subject is a human.