Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-08-19
2002-04-16
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S560000, C514S557000, C514S568000
Reexamination Certificate
active
06372793
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of neurological dysfunction and, more particularly to a neurological disease characterized by impairment of neuromodulator function, as in Parkinson's disease.
BACKGROUND OF THE INVENTION
Parkinson's disease (PD) is characterized by tremors, hypokinesia, rigidity and abnormal posture as the principal visible symptoms. The tremors in PD are of the resting type, since they occur when the muscles are in a state of relaxation. Its main pathological feature is the degeneration of dopaminergic neurons which have their cell bodies in the substantia nigra and their terminals projecting into the neostriatum. Dopamine is thus significantly depleted in the neostriatum of PD patients. Changes to the substantia nigra and the neostriatal complex are linked to the tremors seen in PD. Compounds that damage the nigrostriatal dopaminergic system and cause hypokinesia, rigidity and tremors have the potential to be used as models for studying PD. Chemical agents such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) damage the nigrostriatal dopaminergic neurons and are widely used to induce symptoms of PD. The effectiveness of these compounds rely on their ability to cause significant damage to the nigrostriatal dopaminergic system. The levels of symptoms are apparently dependent on the degree of nigrostriatal damage, which is somewhat difficult to control. As a result, the symptoms produced by these agents are predominantly rigidity, hypokinesia and poverty of movements and are not always consistent. Tremor, the most conspicuous symptom of PD is not a characteristic feature of the MPTP and 6-OHDA models.
Despite the abundant knowledge regarding the behavioral and pathological features of PD, the actual cause of Parkinson's disease symptoms and neurodegeneration remains elusive. Although dopamine depletion has been shown to be a common feature, it is unclear whether this is due mainly to the loss of the dopamine producing cells themselves. PD models such as that of MPTP, a synthetic compound, do not explain cases of familial Parkinsonism. The present model, however, is based on S-adenosylmethionine (SAM), an endogenous compound that is widely distributed within body tissues. This implies that environmental and genetic factors that induce aberrant changes in its synthesis and use may result in disease conditions. It has been reported that injecting SAM into the lateral ventricles of rodents caused the principal symptoms observed in PD (Charlton, 1990, Charlton and Crowell, Jr., 1995, Charlton and Way, 1978, Crowell, Jr. et al, 1993). Most importantly, tremors were routine and always in association with hypokinesia, rigidity and abnormal posture. SAM injections also caused dopaminergic system degeneration as depicted by the loss of tyrosine hydroxylase immunoreactivity in the nigrostriatum and forebrain (Charlton, 1997).
Without a known cause, no cure or preventive measures have been derived for PD. Clinical management of PD has often involved the use of L-DOPA (Pfeiffer, 1998), an intermediate in the dopamine biosynthetic pathway. The general consensus is that L-DOPA, which is more accessible to the central nervous system than dopamine, is taken up by dopaminergic neurons and enzymatically converted to the active neurotransmitter, thus replenishing the depleted dopamine. It has been proposed that SAM-dependent methylation of dopamine by catechol-o-methyltransferase (COMT) may also deplete DA. COMT inhibitors are therefore being explored as PD medications (Pfeiffer, 1998).
SAM-dependent methylation of molecules capable of altering dopaminergic transmission is by no means limited to DA and its metabolites. Nucleic acid methylation is believed to influence gene expression (Chiang et al. 1996). Deleterious changes in gene regulation may precipitate neurodegeneration similar to that encountered in PD. Also, since many studies have concentrated on events leading to the synthesis and release of dopamine, defects in such important phenomena as the transmission of signals from the post synaptic receptors following dopamine receptor binding are yet to be explored for possible links to PD.
Following release, dopamine initiates a chain of events by binding to the post synaptic dopamine receptor. The dopamine receptors belong to a class of membrane-spanning receptors that interact with the GTP-binding proteins known as heterotrimeric G-proteins (Gudermann et al, 1996). Multiple forms of the respective monomers exist with varying degrees of amino acid sequence similarity. Of the three subunits, the &ggr;-subunit undergoes the post-translational modification with either a C15 (trans,trans-farnesyl) or a C20 (all trans-geranylgeranyl)isoprenyl unit. A consensus amino acid sequence (CaaX, where C is cysteine, a is any aliphatic amino acid and X is the carboxyl terminal amino acid) directs the S-prenylation of a cysteine residue (Sinensky and Lutz, 1992). The terminal tripeptide is proteolytically removed (Hrycyna and Clarke, 1992) thus exposing a C-terminally prenylated protein that is capable of undergoing reversible SAM-dependent methylation (Perez-Sala et al, 1991). The &ggr;-subunits, which vary in size from 5 to 7.5 kDa (Cali et al, 1992), exist in a stable heterodimer complex with the &bgr;-subunit, the &bgr;&ggr;-complex only transiently interacting with the &agr;-subunit (Clapham and Neer, 1997). The &agr;-subunit and the &bgr;&ggr;-complex interact with various cellular effector enzymes and ion channels (Clapham and Neer, 1997). For example, the &bgr;&ggr;-complex was found to inhibit the activity of Ca
2+
/calmodulin-stimulated type-I adenylylcyclase but increased that of stimulatory recombinant &Ggr;&agr;-stimulated type-II adenylyl cyclase (Iniguez-Lluhi et al., 1992). These effects on the enzyme activities were found to be dependent on the C-terminal isoprenylation (Iniguez-Lluhi et al., 1992). The &bgr;&ggr;-complex also binds to and influences the activity of voltage-dependent calcium channels (De Waard et al., 1997) and binds to immobilized Raf-1 protein kinase with a nanomolar dissociation constant (Pumiglia et al, 1995). It is not clear what role methylation may play in these processes, if any.
Farnesylcysteine (FC) and geranylgeranylcysteine (GGC) analogs that mimic the C-terminal portion of the prenylated G-protein &ggr;-subunit influence a variety of cellular processes. For example, farnesylthiosalicylate (FTS) increased intracellular calcium concentrations of differentiated HL60 cells and stimulated superoxide release by HL60 cells and polymorphonuclear leukocytes (Tisch et al., 1996). In neutrophils, FC analogs either initiated or inhibited superoxide-release (Ding et al., 1994). FC analogs inhibited [
35
S]GTP[S] binding to washed membranes of myeloid-differentiated HL60 cells (Scheer and Gierschik, 1993, 1995) and capacitative calcium entry into cells (Xu et al., 1996). Although these compounds are avid methyl acceptors and/or competitively inhibit the SAM-dependent methylation of prenylated proteins (Perez-Sala et al., 1992), the cellular phenomena outlined above are believed to be independent of methylation (Scheer and Gierschik, 1993, 1995, Ding et al., 1994).
The possibility has not been investigated that other molecules involved with dopamine signaling such as the G-protein &ggr;-subunit may indeed be hypermethylated and could account for the observed PD symptoms. Methylation has been exert a strong influence on some physiological phenomena. For example, a strong dependence on methylation for the activation of phosphatidylinositol-specific phospholipase C has been reported (Parish et al., 1995). Methylation inhibitors were found to modulate nutrient-induced insulin secretion from rat islets (Metz et al, 1993), permeabilized HIT-T15 cells (Regazzi et al., 1995) and amylase secretion by pancreatic acini (Capdevila et al., 1997). Strains of
Schizosaccharomyces pombe
with a defective mam4 gene that encodes the prenylated protein methyl transferas
Charlton Clivel G.
Lamango Nazarius S.
Allen Dyer Doppelt Milbrath & Gilchrist, P.A.
Florida Agricultural & Mechanical University
Jarvis William R. A.
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