KYNA and Parkinson's disease
The kynurenine pathway accounts for 80% of non-protein tryptophan metabolism. As it was discussed earlier, it includes an agonist (QUIN) and an antagonist (KYNA) at the NMDA receptors, which can behave as an excitotoxin and as a neuroprotectant agent in the central nervous system. It is well known that endogenous excitotoxins have been implicated in the degeneration of dopaminergic neurons in the substantia nigra pars compacta of patients with Parkinson's disease. Miranda et al. (1997) investigated whether an increased level of the endogenous KYNA can protect nigrostriatal dopamine neurons against QUIN-induced excitotoxin damage. They found that 1.5-fold increasing of the KYNA in the substantia nigra prevented the QUIN-induced reduction in striatal tyr-osine hydroxylase. However, 9 hours following the administration of nicotinylalanine (kynureninase and kynurenine hydroxylase inhibitor) with KYN (KYNA precursor) and probenecid (inhibitor of organic acid transport), a time when whole brain KYNA levels had decreased 12-fold, QUIN injection produced a significant depletion in striatal tyro-sine hydroxylase. Thus, it was demonstrated that increases in endogenous KYNA level can prevent the loss of nigrostriatal dopami-nergic neurons resulting from a focal infusion of the excitotoxin QUIN (Miranda et al., 1997). This elevated KYNA level could also prevent the contralateral turning behaviour seen following QUIN administration (Miranda et al., 1999).
Altered KYNA metabolism was found in red blood cells and in plasma in patients with Parkinson's disease: KAT I and II activity were lower in the plasma while KAT II activity were increase in red blood cells. This enhancement of KAT II activity may mediate a protective response against excitatory neurotoxic effects (Hartai et al., 2005).
Altered glutamatergic neurotransmission appears to be central to the pathophysiology of Parkinson's disease. Both NMDA-sensitive and non-NMDA-sensitive glutamate receptors contribute to excitatory postsynaptic currents of dopamine-containing neurons and may play a critical role in the physiology as well as pathology related to these neurons (Mereu et al., 1991). Glutamate may act via ionotropic receptors within striatum to regulate dopamine synthesis, whereas it may influence dopamine release via an action on receptors in substantia nigra (Zigmond et al., 1998). Both spontaneous and evoked dopamine release in the striatum are under the local tonic excitatory influence of glutamate (Kulagina et al., 2001).
Wu et al. (2000) supported the hypothesis that ionotropic receptors can inhibit impulse-dependent dopamine release by the mechanism that acts locally within the striatum. This finding contrasts with previous reports that glutamate can excite impulse-independent do-pamine release. This extends earlier findings that glutamate may both excite and inhibit subcortical dopamine systems by suggesting that the excitatory and inhibitory actions of striatal ionotropic glutamate receptors are specifically associated with impulse-independent and impulse-dependent dopamine release (Wu et al., 2000c).
Different doses of glutamate receptor antagonists were tested against MPP+ neuro-toxicity on dopaminergic terminals of rat striatum. KYNA, which is a non-selective antagonist of glutamate receptors, partially protected dopaminergic terminal degeneration while dizocilpine, a non-competitive channel blocker of the NMDA receptors, failed to protect dopaminergic terminal from MPP+ toxicity. These findings suggest that protective effect of KYNA against the toxic MPP+ on dopaminergic terminals are mediated mainly through the AMPA-kainate subtype (Merino et al., 1999).
Homeostatic interactions between dopa-mine and glutamate are central to the normal physiology of the basal ganglia. This relationship is altered in Parkinsonism and in levodopa-induced dyskinesias, resulting in an upregulation of corticostriatal glutamater-gic function. Using Ro 61-8048, a kynure-nine 3-hydroxylase inhibitor which resulted in an increased level of KYNA, with levo-dopa produced a moderate but significant reduction in the severity of dyskinesias while maintaining the motor benefit. This result suggests a promising novel approach for managing levodopa-induced dyskinesias in Parkinson's disease (Samadi et al., 2005). Nerve cells in the substantia nigra pars compacta are known to express tyrosine hydro-xylase. It was shown that the dopaminergic neurons of this region express also kynurenine aminotransferase (KAT), the enzyme taking part in the formation of KYNA. It was demonstrated that after MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treatment, KAT-I expression was decreased in the substantia nigra (Knyihar-Csillik et al., 2004).
Dopaminergic stimulation caused a functionally significant decrease in the concentration of KYNA: L-DOPA effected a dose-dependent, transient reduction in striatal kynurenate, reaching the nadir of —37.5% 1.5 after the drug administration. This effect was abolished in animals with a 6-hydroxy-dopamine-induced lesion of the nigrostriatal pathway, but was not influenced by a prior striatal quinolinate lesion. These data confirm the dopaminergic control of striatal KYNA formation and suggest that the interactions are mediated by astrocytic dopamine receptors. This might provide a link among the do-paminergic, glutamatergic and cholinergic neurotransmission in the normal and diseased striatum (Wu et al., 2002).
It is well known that Parkinson's disease results from a progressive loss of dopaminer-gic neurons of the substantia nigra. Clinical symptoms only appear when neuronal cell death exceeds 50-60%. This late appearance is due to compensatory mechanisms. It is possible that glutamatergic inputs to the substantia nigra may be implicated in this masking of this disease. Reversible pharmacological blockage of this input effect the appearance of motor disturbances. This blockade could lead to presymptomatic diagnosis of Parkinson's disease (Bezard et al., 1997a, b).
Ogawa et al. (1992) investigated the concentration of the tyrosine and tryptophan metabolites in the frontal cortex, putamen and substantia nigra pars compacta in Parkinson's diseased and control brain tissue. Dopamine concentration was significantly decreased in the putamen and substantia nigra of diseased tissue, regardless of L-DOPA therapy. KYN and KYNA concentrations were lowered in each region of the diseased groups (with or without L-DOPA-treatment) than in the control group, but the molar ratios of TRP to KYN and KYN to KYNA were unchanged among three groups. In contrast, 3-hydroxy-kynurenine concentration was increased in the putamen in the Parkinson's disease without L-DOPA-group and in the three regions of the brain tissue with Parkinson's disease with L-DOPA therapy (Ogawa et al., 1992). However, the concentration of total serotonin, 3-hydroxytryptophan, KYN and 3-hydroxy-kynurenine decreased significantly in diseased patient according to the study of Tohgi. 3-Hydroxykynurenine concentration had significant positive correlations with L-DOPA doses (Tohgi et al., 1993a, b). Neopterin concentration and KYN/TRP ratios were increased both in serum and cerebrospinal fluid of patients as compared to controls. Furthermore, significant correlations existed between the neopterin level and KYN/TRP ratio. This suggests the activated cell-mediated immune response in subgroup of patients with advanced Parkinson's disease (Widner et al., 2002b).
Catalepsy-akinesia with rigor- and reduced locomotion show similarities with symptoms of Parkinson's disease. 7-chloro-KYNA dose-dependently counteracts dopa-mine D2 receptor-mediated catalepsy, induced by haloperidol, but it has not influence on locomotion and on dopamine D1 receptor-mediated catalepsy. These findings are surprising since NMDA receptor antagonists counteract both dopamine D1 and D2 receptor-mediated catalepsy. D1 and D2 receptors are located on different populations of neurons, so it may be supposed that these different neuronal populations have different sensitivity for ligands binding at the glycine site of the NMDA receptors (Kretschmer et al., 1994; Ossowska et al., 1998).
The subthalamic nucleus has been implicated in movement disorders in Parkinson's disease because of its pathological mixed burst firing mode and hyperactivity. In physiological conditions the bursty pattern of this nucleus has been shown to be dependent on slow wave cortical activity, thus glutamate afferents might be involved in this bursting activity. But according to a recent study glu-tamatergic-receptors blockade does not regularize the slow wave sleep bursty pattern of subthalamic nucleus (Urbain et al., 2004).
QUIN and Parkinson's disease
Excitotoxins constitute a group of agents are capable of activating excitatory amino acid receptors and producing axon-sparing neuronal lesions. QUIN is a pyridine-dicarboxylic acid which is localized to glia and immune cells, and its content increases with ages. Focal injections of QUIN into the nucleus basalis magnocellularis produced sustained loss of cholinergic neuron markers in the neocortex and amygdala. This resulted in an impairment of performance of memory-related tests. In the striatum focal QUIN injections have been found to largely replicate the neurotransmitter deficits prevailing in Huntington's disease. QUIN is also highly damaging to the striato-pallidal encephalinergic neurons (Jhamandas et al., 1994). Autoradiographic techniques were used to study distribution of histamine H2-receptors in the brains of patients affected by human neurodegenerative pathologies compared with control cases. The highest level of histamine binding sites in control cases were found in the caudate, putamen and accumbens nuclei. In Huntington's chorea the levels of histamine H2-receptor binding sites were found to be markedly decreased in virtually all region examined, while in Parkinson's disease the levels of histamine H2-receptor binding sites were not different from those of control cases. These results were comparable with those obtained from unilaterally neurotoxin-lesioned guinea pigs. Similar losses of binding sites were observed in QUIN-lesioned striatal intrinsic neurons, whereas lesioning dopaminergic cell bodies in the substantia nigra with 6-OH-dopamine did not produce any significant change. These results strongly suggest that histamine H2-receptors are expressed by striatal neurons, which degenerate in Huntington's chorea, but not by nigral dopaminergic neurons and may play a role in the regulation of the intact striatonigral pathway (Martinez-Mir et al., 1993).
Macaya et al. (1994) observed that an axon-sparing injury to the developing stria-tum induced by excitotoxin QUIN resulted in a decrease in dopaminergic neurons in the substantia nigra pars compacta of the adult. As the striatum is a major target for the sub-stantia nigra pars compacta dopaminergic system, they have hypothesized that a decrease in the size of the striatal target during development may result in an induced regressive event in this region. It was concluded that developmental striatal excitotoxic injury is associated with induced apoptotic cell death in substantia nigra (Macaya et al., 1994). Furthermore, it was found that induction of apoptotic cell death was largely restricted to the first 2 postnatal weeks. After that time induction of the death was abated (Kelly and Burke, 1996). Increased expression of cyclin-dependent kinase 5 was observed in this induced apoptotic neuron death (Henchcliffe and Burke, 1997). It was demonstrated that destruction of the intrinsic striatal neurons by a local injection of QUIN dramatically enhanced the magnitude of substantia nigra pars compacta apoptosis and resulted in a low number of adult dopaminergic neurons, strengthening the apoptotic nature of the observed developmental cell death in this region. Later, it was supported that the overexpression of the anti-apoptotic protein Bcl-2 attenuated both natural and QUIN-induced apoptosis. Thus, developmental neuronal death plays a critical role in regulating the adult number of dopaminergic neurons in the substantia nigra pars compacta (Jackson-Lewis et al., 2000).
Multiple system atrophy of the striato-nigral degeneration (MSA-SND) type is increasingly recognized as major cause of neurodegenerative Parkinsonism. Previous attempts to mimic MSA-SND pathology in rodents have included sequential injections of 6-OH-dopamine and QUIN into medial forebrain bundle and ipsilateral striatum (''double toxin-double lesion'' approach). Preliminary evidence in rodents subjected to such lesions indicates that embryonic transplantation may partially reverse behavioural abnormalities. Intrastriatal injections of MPP+ (a mitochondrial toxin) results in (secondary) excitotoxic striatal lesion and subtotal neuronal degeneration of ipsilateral substantia nigra pars compacta producing MSA-SND-like pathology by a simplified ''single toxin-double lesion'' approach. Comparative studies of human SND pathology and rodent striatonigral lesions are required in order to determine the rodent models most closely mimicking the human disease process (Wenning et al., 1999, 2000).
Injection of excitotoxin QUIN into the striatum has been extensively used as an experimental model of Huntington's disease, while injection of 6-OH-dopamine into the dopaminergic nigrostriatal pathway provides a well established model of Parkinson's disease. Intrastriatal application of QUIN produced major changes in cytochrome oxidase (decrease) and active glycogen phosphorylase (increase) histochemistry at the level of stria-tum and of most of the other basal ganglia nuclei. Although attenuated over time, these changes persisted up to one year after the lesion. On the contrary, after intrastriatal injection of 6-OH-dopamine no remarkable changes were observed in these 2 metabolic markers staining. This study illustrates the discrepancies between the morphological changes and metabolic changes that are induced when using these experimental models of neurode-generative disorders (Levivier and Donaldson, 2000).
Alteration in the isoprenoid metabolite digoxin has been reported in neuronal degeneration (Parkinson's disease), functional neuropsychiatric disorders (schizophrenia and epilepsy) and immune-mediated disorders (e.g. multiple sclerosis). Digoxin, an endogenous Na+ -K+ ATPase inhibitor, secreted by the hypothalamus, was found to be elevated and red blood cell membrane Na+-K+ ATPase activity was found to be reduced in all these disorders. Digoxin can also preferentially upregulate tryptophan transport over tyrosine, resulting an increased levels of depolarizing tryptophan catabolites, serotonin, QUIN, nicotin, and decreased levels of hy-perpolarizing tyrosine catabolites, dopamine, noradrenalin, morphine, contributing to membrane Na+ -K+ ATPase inhibition. It can result in increased level of intracellular Ca2+ and reduced level of Mg2+ leading to glutamate excitotoxicity (Kurup and Kurup, 2002, 2003a). Hence, the dysfunctional isoprenoid pathway and related cascade are very important in the pathogenesis of Parkinson's disease. This hypothalamic digoxin-mediated model for this disease is also postulated (Kurup and Kurup, 2003b).
Behavioural and electrophysiological methods were used to investigate the effects of combining a unilateral QUIN lesion of the entopeduncular nucleus with a striatal transplant of fetal ventral mesencephalic tissue in 6-OH-dopamine hemi-lesioned rat model for Parkinson's disease. The results of the experiments show enhanced motor and neuronal sensitivity to amphetamine after the interven tion suggesting that such a multiple approach might prove more beneficial than one-site intervention targeting either the entopedun-cular nucleus or the striatum (Olds et al., 2003). Parkinson's disease (hypokinetic disorder) and Huntington's disease (hyperkinetic disorder) share the fact that in the motor pathways the dysfunction starts in the stria-tum. A study aimed to determine whether the introduction of a mild Huntington's disease condition in the Parkinson's disease striatum can counter the hypokinetic condition. The findings suggest that the shift from ipsilateral rotation to oral stereotypy after QUIN administration in medial, central and lateral striatum was due to reduced striatal output caused by a loss of projection neurons, insufficient to induce Huntington's disease symptoms, but sufficient to counter the Parkinson's disease condition (Olds et al., 2005). This result was found when QUIN was injected in globus pallidus internus (Lonser et al., 1999).
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