enkephalin--leucine-2-alanine and Parkinson-Disease

Hypofunction of the endogenous opioid, dopamine and iron systems are implicated in the pathogenesis of Restless Legs Syndrome (RLS). Therefore, we probed the interrelationship of these 3 systems in an in vitro model. Cell cultures of the substantia nigra (SN) of Sprague-Dawley rats were established and the cells were determined to be primarily dopaminergic. The numbers of cells surviving under different concentrations of the iron chelator desferoxamine were reduced in a concentration and time dependent manner (p<0.01 at day 10, n=19). The cell death was determined to be apoptotic and DNA analysis revealed that 48-hour 100 μM desferoxamine exposure caused DNA fragmentation of the cells. Pre-administration of the δ-opioid peptide [D-Ala2, D-Leu5]Enkephalin (DADLE) significantly protected the SN cells from damage by iron deficiency (n=6, p<0.01). Our previous studies indicate that the DNA-damage induced apoptosis family gene P53 is activated in this model and that pre-exposure to DADLE prevents this activation. The implications of this model are that in RLS patients with iron deficiency, dopaminergic system dysfunction may result and an intact endogenous opioid system or opioid treatment may protect the dopamine system from dysfunction. Implications of this model for Parkinson's Disease are also briefly discussed.

Topics: Analgesics, Opioid; Anemia, Iron-Deficiency; Animals; Animals, Newborn; Apoptosis; Cell Death; Cells, Cultured; Cytoprotection; Enkephalin, Leucine-2-Alanine; Iron Chelating Agents; Iron Deficiencies; Parkinson Disease; Rats; Rats, Sprague-Dawley; Restless Legs Syndrome; Substantia Nigra

A compound that triggers hibernation in ground squirrels can also protect brain cells from the lack of oxygen following a stroke.

Topics: Animals; Enkephalin, Leucine-2-Alanine; Hibernation; Parkinson Disease; Rats

A major problem in neural transplantation therapy is poor survival of grafted cells, which may be due to low cell viability prior to transplantation or scarce trophic factors available to the cells following transplantation. Recently, the delta enkephalin analogue [D-Ala(2),D-Leu(5)]-enkephalin (DADLE) has been demonstrated to protect against, as well as to reverse methamphetamine-induced loss of dopamine transporters. Here, we show that pretreatment with DADLE (0.0025, 0.005, 0.01 g/ml) dose-dependently enhanced cell viability of cultured primary rat fetal mesencephalic cells. In addition, DADLE administration in adult rats (4 mg/kg every 2 h, 4 injections, i.p.) prior to 6-hydroxydopamine lesions of the medial forebrain bundle, significantly reduced the severity of loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra 1 month post-lesion. This is the first report suggesting that DADLE can be used as a supplement factor for improving the cell viability of fetal mesencephalic cells and as a protective agent against neurotoxicity in a Parkinson's disease model.

Topics: Adrenergic Agents; Age Factors; Animals; Brain Tissue Transplantation; Cell Death; Cell Survival; Cells, Cultured; Dopamine; Enkephalin, Leucine-2-Alanine; Fetus; Male; Nerve Degeneration; Neurons; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley; Substantia Nigra; Time Factors

The specific binding of [3H]neurotensin, [3H]substance P, [3H]D-Ala2-D-Leu5-enkephalin (delta receptors) and [3H]-Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (mu receptors) were studied in membrane preparations of caudate nucleus, putamen, globus pallidus and substantia nigra from patients with Parkinson's disease and from age-matched controls. The density of neurotensin receptors was decreased in globus pallidus (lateral and medial segments) in parkinsonian brain. Substance P receptors were reduced in the putamen (anterior and posterior) and in lateral globus pallidus in Parkinson's disease. There was a reduction in the density of opioid receptors in posterior putamen and in mu receptors in caudate nucleus and putamen (anterior and posterior). No differences in neuropeptide receptor binding were observed in substantia nigra from parkinsonian brains compared with control subjects. The reductions in neuropeptide receptor density were less marked than the decrease in caudate and putamen content of dopamine and its metabolites. This suggests that neuropeptide receptors are only partially localized to striatal dopamine terminals.

Topics: Adult; Aged; Amino Acid Sequence; Analgesics; Basal Ganglia; Biogenic Monoamines; Dopamine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Female; Humans; In Vitro Techniques; Male; Middle Aged; Molecular Sequence Data; Parkinson Disease; Receptors, Neurokinin-1; Receptors, Neurotensin; Receptors, Opioid, delta; Receptors, Opioid, mu