neurokinin-a and Parkinson-Disease

Parkinson's disease (PD) is a serious motor disorder and it is the second most common brain degenerative disease in human. PD is known to be caused by degeneration of dopamine neurons in the substantia nigra but the cause of cell death is largely unknown. Mammalian neurokinins [NKs] are a group of neuropeptides that include substance P (SP; neurokinin-1, NK-1), substance K (SK; NK-2; neurokinin A), and neuromedin K (NK; NK-3; neurokinin B). Their biological effects as neurotransmitters, neuromodulators, or neurotrophic-like factors are mediated by three distinct neurokinin receptors, namely SP receptor (SPR: NK-1 receptor, NK-1R), SKR (NK-2R), and NKR (NK-3R). Several lines of evidence have indicated that neurokinins are implicated in the pathogenesis of PD. First, decreases of SP level and SP-immunoreactivity have been found in nigral and striatal tissues of animals with PD and postmortem PD patients. Second, NKs exert neuroprotective effects on neurons. In addition, NK receptors, namely NK-1 and NK-3 receptors, are abundantly localized in dopaminergic and cholinergic neurons of the basal ganglia, indicating that these neurons are under the physiological regulation of NKs. Moreover, modulation in motor activity occurred in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, PD animal model, after systemic administration of NK receptor agonists. NKs and NK receptors, therefore, might be important molecules that are associated with functions and survival of neurons in the basal ganglia, in particular the dopamine neurons. Further studies should be devoted to elucidate the functional roles of NK systems in (a) the neuropathogenesis and neuroprotection during the course of PD, (b) the efficacy of NK receptor drugs towards PD, and (c) potential therapeutic intervention that targets at the prevention or treatment of PD.

Topics: Animals; Antiparkinson Agents; Basal Ganglia; Humans; Neurokinin A; Neurokinin B; Parkinson Disease; Peptides; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3

Immunoreactive neurokinin A was measured in the cerebrospinal fluid of twelve patients with Parkinson's disease and eleven normal subjects, using a sensitive and precise extraction/concentration radioimmunoassay method. The mean value obtained in Parkinson's disease patients (13.2 +/- 4.6 pmol/l) was lower than that of the controls (17.4 +/- 5.9). The tendency toward a significant decrease (p = 0.085) found in this preliminary study could indicate that neurokinin A containing neurons are involved in the pathophysiology of Parkinson's disease. In addition, the establishment of reference values for neurokinin A in cerebrospinal fluid may provide a basis for further studies of this neuropeptide in neurological disorders.

Topics: Aged; Female; Humans; Male; Middle Aged; Neurokinin A; Parkinson Disease; Radioimmunoassay; Reference Values

Brain tissue levels and in vivo release of substance P (SP) and neurokinin A (NKA) and GABA were measured bilaterally in striatum and substantia nigra of the rat, after a unilateral 6-hydroxydopamine lesion of the nigro-striatal dopamine pathway. Sham injected animals served as controls. The dopamine denervation decreased the tissue levels of SP in striatum (-38%) ipsilateral to the lesion and in substantia nigra both ipsi- (-54%) and contralateral (-38%) to the lesion. NKA was not significantly changed in the striatum, but decreased (like SP) in the substantia nigra both ipsi- (-50%) and contralateral (-40%) to the lesion. GABA tissue levels increased in the denervated striatum (+20%) and remained unchanged in substantia nigra at both sides. The extracellular levels of SP, NKA and GABA were measured with microdialysis in vivo at basal conditions and during stimulation with potassium administered locally via the microdialysis probe. The stimulated release of SP and NKA in the substantia nigra ipsilateral to the lesion was compared to in sham operated animals reduced with 39% and 64%, respectively, while no change in SP or NKA release was detected in the striatum. The basal release of GABA in the striatum was increased with 296% and with 76% during stimulation in the dopamine denervated striatum, while no change in GABA basal or stimulated release was detected in the substantia nigra. We suggest that the increased GABA release in the dopamine denervated striatum may be due to a decreased dopamine mediated inhibition of local GABA neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Corpus Striatum; Dopamine; gamma-Aminobutyric Acid; Hydroxydopamines; Male; Neurokinin A; Oxidopamine; Parkinson Disease; Rats; Rats, Inbred Strains; Substance P; Substantia Nigra; Tachykinins