1. Technical Field
The present invention relates a pharmaceutical composition for prevention or treatment of degenerative neurological brain disorders, such as Parkinson's disease, Alzheimer's dementia (senile dementia), stroke, Lou Gehrig's disease, Pick's disease, Creutzfeldt-Jakob disease, Huntington's disease, progressive supranuclear palsy, spinocerebellar degeneration, cerebellar atrophy, multiple sclerosis, post-traumatic stress disorder, and amnesia.
2. Description of the Related Art
Degenerative neurological brain disorders representative by Parkinson's disease, Alzheimer's disease, dementia, stroke, etc. are well known to be derived from cell death followed by damage and loss of nerve cells (‘neurons’), as an ultimate cause. For instance, in the case of Parkinson's disease, dopaminergic neurons present in substantia nigra of mesencephalon are selectively lost so as to cause dysfunction of basal nuclei participating in movement functional tissues, and lead to continuous trembling, stiffness, slow oscillation, unstable posture, etc. (Nimi et al., Clinical and physiological characteristics of autonomic failure with Parkinson's disease. Clin Autonom Res 9(1999), 139-144; Dawson et al., Molecular pathways of neurodegeneration in Parkinson's disease. Science (2003), 819-822).
Active oxygen is indicated as a major cause of neuron death in relation to degenerative neurological brain disorders. This active oxygen refers to oxygen having strong oxidation activity, which is received in a living body during breathing and used for oxidation, generated in different metabolic processes, attacks bio-tissues in the body and damages cells. Such active oxygen may cause irreversible damage in DNA, cell formable proteins and lipids in living cells (Valko et al., Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 39(2007), 44-84). In particular, when active oxygen is generated in a large quantity in brain cells, oxidative stress occurs and causes changes in the structure and function of mitochondria in the cell, in turn causing neurological brain disorders such as Parkinson's disease, Alzheimer's disease, etc. (Knott et al., Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci., 9(2008), 505-18).
Alternatively, with respect to degenerative neurological brain disorders including Parkinson's disease, a lot of study results regarding the role of glutamate as an excitatory neurotransmitter and an abnormally accumulated protein have been reported. It is now known that glutamate performs a physiologically important role but, when it is excessively secreted, may cause damage of neurons, thus being party to the cause of specific diseases, i.e., degenerative neurological brain disorders including Parkinson's disease. (Samuel et al., Localization of N-methyl-D-aspartate receptors in the rat striatum: effects of specific lesions on the [3H] 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid binding. J Neurochem 1990; 54:1926-1933; Weihmuller et al., Elevated NMDA receptors in Parkinsonian striatum. Neuroreport 1992; 3:997-980). Furthermore, abnormal accumulation of protein which is characteristic of degenerative neurological brain disorders can be observed. For example, in the case of Parkinson's disease, it was discovered that α-synuclein protein is a major component to form a pathogenic probe of Parkinson's disease, i.e., Lewy body (Spillantini et al., Alphα-synuclein in Lewy bodies. Nature 388(1997), 839-840). The protein described above may be toxic by itself or indirectly express toxicity by generating active oxygen, to hence cause cell death (‘apoptosis’).
Currently, a method for treatment of Parkinson's disease has yet to be developed and a dopamine precursor, L-dopa or dopamine receptor promoter, is simply known to function as a symptom enhancer. However, this treatment drug cannot prevent continuous loss of dopaminergic neurons and, as a result, may involve a sharp deterioration of efficacy within 5 to 6 years. In addition, side effects including movement dysfunction are increased and L-dopa problems known as ‘on-off phenomenon’ at the late period of a disease are greatly increased, hence leading to death within 10 to 15 years after the onset of symptoms (Vautier S, Milane A, Fernandez C, Buyse M, Chacun H, Farinotti R, Interactions between antiparkinsonian drugs and ABCB1/P-glycoprotein at the blood-brain barrier in a rat brain endothelial cell model. Neurosci Lett. 442(2008), 19-23; Molecular mechanisms of 6-hydroxydopamine-induced cytotoxicity in PC12 cells: Involvement of hydrogen peroxide-dependent and -independent action. Free Radical Biology & Medicine 42(2007), 675-685).
Meanwhile, it is well known that Parkinson's disease generally includes movement dysfunction as a representative symptom. Moreover, cognitive impairments of varied levels, including dysfunction of autonomic nervous system, sensory nervous system disorders and dementia, are also observed (Morris et al., Planning and spatial working memory in Parkinson's disease. J Neurol Neurosurg Psychiatry, (1988) 757-66; Robbins et al., Cognitive deficits in progressive supranuclear palsy, Parkinson's disease, and multiple system atrophy in tests sensitive to frontal lobe dysfunction. J Neurol Neurosurg Psychiatry, (1994) 79-88). Such cognitive impairments have traditionally been ignored and undervalued since Parkinson's disease has been considered to be a disease involving movement dysfunction. However, cognitive impairments or dementia expressed by a patient with progressive Parkinson's disease are currently considered to be obvious abnormal findings that appear in Parkinson's disease (Emre, Dementia associated with Parkinson's disease. Lancet Neurol., (2003) 229-37; Emre, Dementia in Parkinson's disease: cause and treatment. Curr Opin Neurol., (2004) 399-404). In fact, it is known that about 20 to 40% of Parkinson's disease patients suffer from dementia and the incidence of the dementia is up to 6 times higher than in healthy persons (Mortimer et al., Relationship of motor symptoms to intellectual deficits in Parkinson's disease. Neurology, (1982) 133-7; Emre, Dementia associated with Parkinson's disease. Lancet Neurol., (2003) 229-37).
However, according to conventional studies, it has been reported that the administration of Levodopa (L-dopa) for the improvement of cognitive function in dementia accompanying Parkinson's disease has not been conducted on a large scale. Improvement and positive activity with regards to mood, as well as beneficial effects useful in information processing by dopaminergic neurotransmission and working memory, are partially demonstrated. However, it is known that the main goal, that is, delayed deterioration of cognitive function, cannot be achieved (Pillon et al., Cognitive deficits and dementia in Parkinson's disease. 2 ed. Amsterdam; Elsevier Science; 2001).
Accordingly, it is now urgently required to develop a drug for nerve protective treatment which is capable of preventing or delaying the progress of a disease and a drug for improvement of various degenerative neurological brain disorders as well as dementia symptoms of Parkinson's disease, on the basis of a correct molecular pathological mechanism of Parkinson's disease.
USPTO Backgrounds
USPTO Backgrounds