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Title:  Polyamine treatment of neurological disorders

United States Patent:  6,576,672

Issued:  June 10, 2003

Inventors:  Murphy; Michael A. (5619 Chelsea Ave., La Jolla, CA 92037)

Appl. No.:  486310

Filed:  February 23, 2000

PCT Filed:  August 21, 1998

PCT NO:  PCT/US98/17301

PCT PUB.NO.:  WO99/08519

PCT PUB. Date:  February 25, 1999


2,3,2 Tetramine (3,7-diazanonane-1,9-diamine) is propounded for treatment of Parkingson's Disease and dementias characterized by mitochondrial damage in view of this compound's ability to completely neutralize the dopamine-depriving effect of MPTP in laboratory animals up to 12 hours post MPTP injection, and to retain partial protection at suboptimal tissue levels for up to 36 hours. The effect of injecting combinations of MPTP and/or reducing agents and/or xenobiotics and/or depigmenting agents on Dopamine, Norepinephrine, Serotonin and Epinephrine levels demonstrated that MPTP and MPP+ act as reducing agents that mobilize copper and calcium, and sequester iron, and that the vulnerability of dopamine to these types of neurotoxins and to xenobiotics and metals can be corrected by administration of 2,3,2 tetramine that appears to redistribute metals between diverse storage pools and free metals in cytosol and regulate receptor mediated events, among other antidotal effects analogous to those of some of the endogenous polyamines.


This invention results from an attempt to look beyond traditional substance replacement therapies in the treatment of degenerative neurological disorders such as dopamine replacement through L Dopa therapy, increasing acetylcholine at post synaptic sites by using anticholinesterase drugs in treating Alzheimer's disease or the supply of growth factors or diffusible neuropeptides such as substance P via cell grafting in treating Parkinson's Disease and Alzheimer's disease.

Instead, the invention is directed to the intrinsic regulation of cellular activities in Parkinson's Disease, Alzheimer's Disease, Guamanian Parkinsonian Dementia, Amyotrophic Lateral Sclerosis, Olivopontine Cerebellar Atrophy, Hereditary Cerebral Hemorrhage--Dutch Type, Amyloid Angiopathy, Batten's Disease, and in the neuronal complications of Binswanger's Disease. An understanding is derived of why particular neurons are primary targets of damage in these diseases, a mechanism of progression from Parkinson's disease to Alzheimer's disease and how differing etiologic events determine the patterns of damage in Parkinson's disease and Alzheimer's disease and Batten's disease versus the relative importance of later events in the cascade in the pathogenesis of Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease) and Guamanian Parkinsonian Dementia. Further understanding is gained of the steps at which diagnostic tests could be developed and where therapy can be employed.

Cascade of Events in Pathogenesis

In Parkinson's Disease mitochondrial DNA is damaged by dopamine and xenobiotics in the presence of reduced levels of naturally occurring polyamines. Polyamines protect DNA from damage by organic molecules by steric interactions. Polyamines competitively block the uptake of xenobiotics. They also induce transcription of growth factors such as nerve growth factor, brain derived neuronotrophic factor. Polyamines regulate the activity NMDA receptor and affect the level of agonism or antagonism at the MK801 ion channel. Polyamines regulate redox homeostasis by binding glutathione. These primary deficits associated with polyamine deficiency cause the dedifferentiation processes of these disease via the changes in growth factor levels or ratios, the rapid entry of calcium via the MK801 ion channel and the metabolic consequences by damaged RNA transcripts causing production of defective cytochromes.

Secondarily defective cytochromes are proteolysed and release enkephalin by products and also release free iron into the mitochondrial matrix. The iron is leached from damaged calcium laden mitochondria into the cytosol of the neurons. NMDA receptor activation causes calcium entry into cells.

Thirdly gross elevation of the free level of a metal such as iron causes displacement of other metals such as copper, nickel, cobalt and lead from sites where they are bound. One or more of these metals overactivate preasapatate proteases which can produce Beta amyloid and tangle associated proteins. In Parkinson's Disease and Alzheimer's Disease there is an increase in free copper levels in the absence of an absolute increase in copper levels or more likely an actual decrease in total tissue copper levels due to its loss in the cerebrospinal fluid. The free copper will activate amine oxidase, tyrosinase, copper zinc superoxide dismutase and monoamine oxidase B. The preaspartate proteases may be activated by several divalent metal ions including such as zinc, iron, calcium, cobalt. The literature on these proteases indicate that zinc and calcium are particularly likely. Given a role for divalent metals in activating pre aspartate proteases and amyloid production as a tertiary event in this model, it is in concordance with the clinical situation whereby patients present with Parkinson's Disease and subsequently Alzheimer's Disease rather than the converse. In Guamanian Parkinsonian Dementia the plaque formation likewise follows motor neuron and Parkinsonian pathology.

More specifically, therapeutic compounds have multiple actions on this cascade of events extending from DNA damage to amyloid production;

a) Competitive inhibition of uptake of xenobiotics at the polyamine transport site, such organic molecules being a cause of DNA damage;

b) Limitation of mitochondrial DNA damage by removal of free copper, iron and nickel ions by the presence of an aliphatic tetramine;

c) Induction of nerve growth factor, brain derived neuronotrophic factor and neuronotrophin-3 gene transcription;

d) Regulation of affinity of NMDA receptors and blockade of the MK801 ion channel;

e) Binding and conservation of reduced glutathione;

f) Maintenance of the homeostasis of the redox environment in brain;

g) Induction of metallothionein;

h) Inhibition of protein kinase C;

i) Non toxic chelation of divalent metals in brain;

j) Regulation of activity of pre-aspartate proteases;

k) Inhibition of superoxide dismutase, amine oxidase, monoamine oxidase B;

l) Regulation of brain polyamine levels in dementias with maintenance of endogenous polyamine levels.

Claim 1 of 14 Claims

What is claimed is:

1. A method of treating Parkinson's, Alzheimer's, Lou Gehrig's, Binswanger's Diseases and, Olivopontine Cerebellar Atrophy in animals through steric protection of DNA, enhancement of transcription of growth factors sequences, regulation of the NMDA receptor and the activity of the MK801 ion channel and other brain cell physiological stabilizing phenomena, said method comprising administering to said animals an effective dose of polyamine taken from a group consisting of cyclic and linear and branched polyamines.

If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.



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