Regulation of tyrosine hydroxylase

Details Regulation of tyrosine hydroxylase Regulation of tyrosine hydroxylase

2001-02-12

2003-09-09

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S018700

Reexamination Certificate

active

06617311

ABSTRACT:

This invention relates to methods of regulating the effect of tyrosine hydroxylase (TH). In particular it relates to increasing the effective amount of TH in the central nervous systems (CNS) for the purpose of increasing TH-mediated dopamine production in the treatment of conditions such as Parkinson's disease.
BACKGROUND
Parkinson's disease is the second most prevalent neurodegenerative disorder after Alzheimer's. It is a chronic and progressive motor system disorder and is distinguished by a tremor at rest, muscular rigidity, a slowness of movement initiation and movement execution and a mask-like appearance to the face.
The cause of this disease is unknown but the symptoms are a consequence of an 80% or greater loss of the dopaminergic neurons (which produce dopamine) in the pars compacta region of the substantia nigra (SNc).
Treatments available at present only target symptoms of the disease. No drugs are currently available to intervene in the disease process. L-dopa is the most commonly employed current treatment (in order to supplement dopamine levels within the CNS), but this has limited and transient efficacy.
TH is a rate limiting enzyme for dopamine production. Upregulation of TH expression will therefore increase dopamine production in the CNS.
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 al in EP 0366638. The suggestion made by Sara et al is that GPE has neuromodulatory properties. 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 TH present in the CNS or being able to intervene in the Parkinson's disease process.
OBJECT OF THE INVENTION
It is an object of this invention to provide new approaches to therapy or prophylaxis which involve directly upregulating the expression of TH and TH-mediated dopamine production in 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 TH present within the CNS 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 effecting an increase in the amount of TH within the CNS of a patient for therapy or prophylaxis of a neurological disorder or condition involving dopaminergic neurons, said method comprising the step of increasing the effective amount of GPE or an analog thereof within the CNS of said patient.
An “increase in the amount of TH” can be effected through upregulation of expression of TH or a reduction in the loss or degradation of TH.
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 TH.
In still a further aspect, the invention provides a method of increasing TH-mediated dopamine production within the CNS of a patient, said method comprising the step of increasing the effective amount of GPE or an analog thereof within the CNS of said patient.
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 pro-drug 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, focal injection or a surgically inserted shunt into the lateral cerebro-ventricle of the brain of the patient.
Conveniently, the amount of TH is increased through the administration of GPE or its analogs in the prophylaxis or therapy of Parkinson's disease.
It is also preferred that the increase of TH-mediated dopamine production is effected as part of therapy or prophylaxis of Parkinson's disease.
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 TH present in the CNS of a patient.
In still a further aspect, the invention consists in the use of GPE or an analog thereof in the manufacture of a medicament for use in increasing TH-mediated dopamine production for treating Parkinson's disease.


REFERENCES:
patent: 5714460 (1998-02-01), Gluckman et al.
patent: 6187906 (2001-02-01), Gluckman et al.
patent: 6294585 (2001-09-01), Brown
patent: 0 366 638 (1990-05-01), None
patent: WO 95/17204 (1995-06-01), None
patent: WO 98/14202 (1998-04-01), None
V. Sara, et al, “Identification 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 & Biophysical Research Communications vol. 165, No. 2, 1989, Dec. 15, 1989 pp. 766-771.
L. Nilsson-Hakansson, et al., “Effects of IGF-1, Truncated IGF-1 And The Tripeptide Gly-Pro-Glu On Acetylcholine Release From Parietal Cortex Of Rat Brain”, Neuroreport, 4, 1111-1114(1993).
J. Saura, “Neuroprotective Effects of Gly-Pro-Glu, the N-terminal Tripeptide Of IGF-1, In The Hippocampus In Vitro”, Neuroreport 10, pp. 161-164 (1999).
V. Sara, “The Biological Role of Truncated 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 (1993).

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