Regulation of neural enzymes

Details Regulation of neural enzymes Regulation of neural enzymes

1999-05-10

2002-04-02

Jarvis, William R. A. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

Reexamination Certificate

active

06365573

ABSTRACT:

This application is a 371 of PCT/NZ97/00132, filed Oct. 6, 1997.
This invention relates to methods of regulating the effect of neural enzymes. It particularly relates to increasing the effective amount of the neural enzymes choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD) and nitric oxide synthetase (NOS) in the central nervous system (CNS).
BACKGROUND OF THE INVENTION
GPE is a tripeptide consisting of amino acids Gly-Pro-Glu. It and its dipeptide analogs Gly-Pro and Pro-Glu were first disclosed by Sara et at in EP 0366638. The suggestion made by Sara et al is that GPE has neuromodulatory properties (the capability of affecting the electrical properties of neurons). GPE has also been established as having neuroprotective properties and therefore having utility in the prevention or inhibition of neural cell death (WO 95/17204).
To date however, there has been no teaching or suggestion of GPE or its analogs having any direct effect on the effective amount of neural enzymes present in the CNS. There has certainly been no suggestion of GPE having the ability to upregulate expression of the neural enzymes, ChAT, GAD and NOS, and/or of their receptors.
ChAT is involved in the synthesis of the neurotransmitter acetyl choline. An ability to upregulate ChAT expression therefore has implications for neural, muscular and neuromuscular therapy and prophylaxis, including where the survival of neural cells is not threatened.
GAD is involved in the synthesis of the important inhibitory neurotransmitter gamma amino butyric acid (GABA). An ability to upregulate GAD expression therefore has implications for neural therapy and prophylaxis.
NOS has multiple functions in the brain, including regulating blood flow, cell metabolism and cell survival. An ability to regulate NOS expression using GPE therefore has implications for neural therapy and prophylaxis, including where the survival of neural cells is not threatened.
It is the object of this invention to provide new approaches to neuronal therapy or prophylaxis which involve directly upregulating the expression of neural enzymes present in the CNS, or at least to provide the public with a useful choice.
SUMMARY OF THE INVENTION
In a first aspect, the invention provides a method of treatment of a patient suffering from or susceptible to a condition in which an increase in the amount of a neural enzyme selected from ChAT, NOS and GAD is desirable, which method comprises the step of increasing the effective amount of GPE or an analog thereof within the CNS of said patient.
In a further aspect, the invention provides a method of increasing the amount of the neural enzyme ChAT in a patient for therapy or prophylaxis of a neurological disorder or condition, said method comprising the step of increasing the effective amount of GPE or an analog thereof within the CNS of said patient.
In still a further first aspect, the invention provides a method of increasing the amount of the neural enzyme GAD in a patient for therapy or prophylaxis of a neurological disorder or condition, said method comprising the step of increasing the effective amount of GPE or an analog thereof within the CNS of said patient.
In yet a further aspect, the invention provides a method of increasing the amount of the neural enzyme NOS in a patient for therapy or prophylaxis, said method comprising the step of regulating the effective amount of GPE or an analog thereof within the CNS of said patient.
“Increasing the amount” of a neural enzyme is through upregulation of expression of the neural enzyme.
By “analog” it is meant the dipeptides Gly-Pro and Pro-Glu as well as any other small peptide which is capable of effectively binding to the receptors in the CNS GPE binds to and of inducing an equivalent upregulatory effect upon the expression of ChAT, GAD or NOS and/or their respective receptors.
Most preferably, it is the effective amount of GPE itself which is increased within the CNS of the patient. This can be effected by direct administration of GPE and indeed this is preferred. However, the administration of compounds which indirectly increase the effective amount of GPE (for example a prodrug which, within the patient is cleaved to release GPE) is in no way excluded.
The active compound (GPE or its analog) can be administered alone or, as is preferred, as part of a pharmaceutical composition.
The composition can be administered to the patient peripherally (for example by a parenteral route such as injection into the peripheral circulation) or can be administered directly to the CNS. This latter route of administration can involve, for example, lateral cerebro-ventricular injection or a surgically inserted shunt into the lateral cerebro ventricle of the brain of the patient.
Conveniently, the expression of CHAT and/or its receptors is upregulated through the administration of GPE or its analogs in the prophylaxis or therapy of one or more of the following:
Motor neuron disease;
Alzheimers disease;
Muscular dystrophy;
Peripheral neuropathies;
Autonomic neuropathies;
Memory loss; and
Neurodegeneration due to aging.
Conveniently, the expression of GAD and/or its receptors is upregulated through the administration of GPE or its analogs in the prophylaxis or therapy of one or more of the following:
postasphyxial seizures;
convulsive disorders such as epilepsy: and
neurodegenerative diseases such as Huntingtons.
Conveniently, the expression of NOS and/or its receptors is upregulated through the administration of GPE or its analogs in the prophylaxis or therapy of one or more of the following:
subarachonoid haemorrahge;
transient ischemic attack;
stroke;
multinfarct dementia;
cerebral vasculitis; and
traumatic brain injury.
In a further aspect, the invention also consists in the use of GPE or an analog thereof in the manufacture of a medicament for use in increasing the amount of ChAT, GAD or NOS present in the CNS.


REFERENCES:
patent: A1 38084/93 (1993-10-01), None
patent: A2 0366638 (1990-05-01), None
patent: WO A1 95/17204 (1995-06-01), None
Sara, V.R. et al. (1989) Indentification of Gly-Pro-Glu (GPE), the aminoterminal tripeptide of insulin-like growth factor 1 which is truncated in brain, as a novel neuroactive peptide, Biochemical and biophysical research Communications, vol. 165, No. 2, Dec. 15, 1989, pp. 766-771.
Nilsson-Hakansson, L.et al. (1993) Effects of IFG-1, truncated IGF-1 and the tripeptide Gly-Pro-Glu on acetylocholine release from parietal cortex of rat brain, NeuroReport, vol. 4, No. 9, Aug. 6, 1993, pp. 1111-1114.
Sara, V.R. et al. (1993) The Biological Role of Truncatted Insulin-like Growth Factor-1 and the Tripeptide GPE in the Central Nervous system, Annals of the New York academy of Sciences, vol. 692, pp. 183-191.
Sara, V.R. et al. (1991) Neuroactive products of IGF-1 and IGF-2 gene expression in the CNS, Molecular Biology and Physiology of Insulin and Insulin like Growth Factors, Editted by Raizada, M.K. and LeRoith, D., Plenum Press, New York, 1991, pp. 439-448.
Gluckman, P.D. et al.(1994) The role of IGF-1 in the response to organ injury-studies in the central nervous system, The insulin-like growth factors and their regulatory proteins, pp. 427-434.

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