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PubMed1983

Effect of 6-hydroxydopamine on bovine adrenal chromaffin cells in culture.

The effect of 6-hydroxydopamine on the catecholamine content and cell morphology of bovine adrenal chromaffin cells in culture was investigated. 6-Hydroxydopamine markedly reduced the catecholamine content of the cultured chromaffin cells after 6 and 24 h exposure. The effect was dose-related, with half-maximal depletion occurring at 2.4 X 10(-5) M. Cells exposed to 6-hydroxydopamine for 3 h and then to normal medium without the drug for 3 h more showed the same degree of toxicity as cells exposed to the drug for the entire 6 h. Ascorbate at high concentrations also exhibited toxicity toward chromaffin cells between 6 and 24 h of exposure. 6-Hydroxydopamine produced marked changes in cell morphology. At 1 h the cells appeared normal, at 3 h the processes were markedly shortened, and at 6 h they were completely retracted. On exposure for 24 h there were gross morphological changes and most cells were detached and free-floating in the medium. The toxicity of 6-hydroxydopamine in bovine adrenal chromaffin cells is discussed.

Adrenal Medulla↗

PubMed1987

Effects of reserpine and 6-hydroxydopamine on the adrenergic and purinergic components of sympathetic nerve responses of the rabbit saphenous artery.

1 The effects of reserpine and of 6-hydroxydopamine on the contractions of the rabbit isolated saphenous artery produced by stimulation of the sympathetic nerves were studied. 2 In vessels exposed to reserpine, substantial contractions to nerve stimulation were recorded despite a 95.7% reduction in the noradrenaline content of the tissue. These responses of the vessel were not significantly affected by the alpha 1-antagonist, prazosin, whereas after desensitization of the P2-purinoceptor with alpha, beta-methylene ATP, no response to nerve stimulation remained. 3 In vessels exposed to 6-hydroxydopamine, no nerve-mediated responses were observed. 4 Noradrenaline-containing nerves were observed by fluorescence histochemistry in control tissues, but were not observed in tissues treated with reserpine or 6-hydroxydopamine. 5 The potencies of ATP and histamine were not significantly affected by reserpine or 6-hydroxydopamine treatment. However, there was a slight supersensitivity to noradrenaline in reserpine-treated and 6-hydroxydopamine-treated vessels compared with that of control vessels. Prazosin was selective for alpha-adrenoceptors, while alpha, beta-methylene ATP was selective for P2-purinoceptors. 6 These results substantiate the finding that ATP and noradrenaline are sympathetic cotransmitters in the rabbit isolated saphenous artery, and demonstrate that ATP can act as a transmitter independently of noradrenaline in this vessel.

Adenosine Triphosphate↗

PubMed1986

Rubidium uptake by mouse pancreatic islets exposed to 6-hydroxydopamine, ninhydrin, or other generators of hydroxyl radicals.

The purpose was to study the toxicity of drugs known to generate free radicals on isolated pancreatic islets. The accumulation of 86Rb+ by mouse pancreatic islets was measured in vitro. Exposing the islets to 6-hydroxydopamine, ninhydrin, or phenazine methosulphate+NADH inhibited the Rb+ uptake, whereas paraquat or acetylphenylhydrazine had no effect. This effect of 6-hydroxydopamine was prevented by either of the hydroxyl radical scavengers, sodium benzoate and mannitol, but not by the non-scavenger, urea; ninhydrin was partially protected against by mannitol but not by benzoate. Protection against 6-hydroxydopamine was also afforded by D-glucose but not by L-glucose or 3-O-methyl-D-glucose; none of the sugars protected against ninhydrin. In damaging islet beta-cells and in being protected against by D-glucose, 6-hydroxydopamine closely resembles the diabetogenic drug, alloxan. It is suggested that protection against alloxan may involve both glucose metabolism and the interaction of glucose with its membrane-located carrier, while protection against 6-hydroxydopamine appears to be unrelated to the hexose carrier mechanism.

Animals↗

PubMed1980

The cardiovascular responses of conscious newborn lambs treated in utero with 6-hydroxydopamine.

Fourteen fetal sheep were treated in utero with a single intramuscular injection or three to four injections of 6-hydroxydopamine. After birth the cardiovascular responses of these lambs to adrenergic drugs were studied and compared with the cardiovascular responses of untreated newborn lambs. Lambs which received three to four injections of 6-hydroxydopamine were more sensitive to the pressor actions of noradrenaline and phenylephrine than were control lambs or lambs which received a single injection of 6-hydroxydopamine. The supersensitivity to noradrenaline persisted in multiple treatment lambs until at least 5 months of age. Lambs which received multiple injections of 6-hydroxydopamine were also subsensitive to the pressor action of tyramine. The sensitivity to the pressor actions of noradrenaline and phenylephrine in lambs which received a single injection of 6-hydroxydopamine lay between that of control and multiple treatment groups. Despite the pharmacological evidence of impairment of sympathetic innervation of peripheral blood vessels plus a lack of responsiveness of these lambs to alpha-adrenergic blockade with phentolamine, treated lambs had arterial pressures and heart rates similar to control lambs. As well, treated lambs showed no impairment in their ability to reflexly regulate heart rate in response to changes in arterial pressure, which is consistent with the recently reported vagal control of the cardiac baroreceptor reflex.

Animals↗

PubMed2005

Angiotensin-converting enzyme inhibition reduces oxidative stress and protects dopaminergic neurons in a 6-hydroxydopamine rat model of Parkinsonism.

It is now established that the brain possesses a local renin-angiotensin system and that angiotensin II exerts multiple actions in the nervous system, including regulation of striatal dopamine release. Furthermore, angiotensin activates NADPH-dependent oxidases, which are a major source of superoxide, and angiotensin-converting enzyme inhibitors, commonly used in the treatment of hypertension and chronic heart failure, have shown antioxidant properties in several tissues. Oxidative stress is a key contributor to the pathogenesis and progression of Parkinson's disease. In the present study, we treated rats with intraventricular injections of the dopaminergic neurotoxin 6-hydroxydopamine and subcutaneous injections of the angiotensin-converting enzyme inhibitor Captopril to study the possible neuroprotective effect of the latter on the dopaminergic system and on 6-hydroxydopamine-induced oxidative stress. Rats treated with Captopril and 6-hydroxydopamine showed significantly less reduction in the number of dopaminergic neurons (i.e., immunoreactive to tyrosine hydroxylase) in the substantia nigra and in the density of striatal dopaminergic terminals than 6-hydroxydopamine-lesioned rats not treated with Captopril. In addition, Captopril reduced the levels of major oxidative stress indicators (i.e., lipid peroxidation and protein oxidation) in the ventral midbrain and the striatum of 6-hydroxydopamine-lesioned rats. Our results suggest that angiotensin-converting enzyme inhibitors may be useful for treatment of Parkinson's disease and that further investigation should focus on the neuroprotective capacity of these compounds.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

Study of the neurotransmitter dopamine and the neurotoxin 6-hydroxydopamine by electrospray ionization coupled with tandem mass spectrometry.

Electrospray ionization combined with tandem mass spectrometry has been applied to a study of dopamine and 6-hydroxydopamine, an important neurotransmitter and a well-known neurotoxin, respectively. Both protonated and deprotonated molecules were observed for the two compounds. Upon collision-induced dissociation of protonated and deprotonated 6-hydroxydopamine molecules, the number of fragmentation pathways observed was greater than that observed with protonated and deprotonated dopamine molecules; the greater proclivity to fragment of the former is due to the 6-substituted hydroxyl group, which is para to the 3-OH group and ortho to the CH2CH2NH2 group. Furthermore, 6-hydroxydopamine showed a greater propensity to oxidize than did dopamine when sample solutions were kept uncovered in the air for 24 h prior to mass spectrometric examination. Radical structures of the four main oxidation products of 6-hydroxydopamine have been suggested on the basis of their product ion mass spectra; one or more of these oxidation products may be responsible for the cytotoxic property of 6-hydroxydopamine.

Dopamine↗

PubMed2000

Pramipexole attenuates the dopaminergic cell loss induced by intraventricular 6-hydroxydopamine.

The D3 preferring dopamine agonist pramipexole has been shown to attenuate the cell loss induced by levodopa in vitro. Pramipexole was herein evaluated in the 6-hydroxydopamine lesion model to determine its in vivo effect. Rats were treated with pramipexole or saline before and after an intracerebroventricular 6-hydroxydopamine injection. In the preliminary study, 6-hydroxydopamine produced a 68% reduction in striatal dopamine and a 62% loss in tyrosine hydroxylase immunoreactive (THir) cell counts in the substantia nigra. Pramipexole treated animals exhibited a 29% and a 27% reduction in striatal dopamine and THir cell counts, respectively. THir cell counts and striatal dopamine were significantly correlated. In the stereological study, 6-hydroxydopamine reduced THir cell counts by 47% in saline treated animals and 26% in pramipexole treated animals. These data demonstrate that pramipexole attenuates the biochemical and THir cell changes normally produced by 6-hydroxydopamine consistent with its neuroprotective actions in vitro.

Animals↗

PubMed1996

Perinatal exposure to morphine: reactive changes in the brain after 6-hydroxydopamine.

The effects of neonatal 6-hydroxydopamine treatment on the brain of control rats and of rats perinatally exposed to morphine were examined. Noradrenaline levels were increased in the pons-medulla, mesencephalon and caudate of 8-week-old control rats lesioned with neonatal 6-hydroxydopamine; perinatal morphine treatment prevented such an increase. In the caudate, there was a loss of dopamine and an increase of serotonin following the neurotoxic lesion; exposure to perinatal morphine prevented the serotonin increase. Brain expression of synapsin I mRNA was particularly abundant in cerebral cortex, hippocampus, dentate gyrus and olfactory bulb. In perinatal morphine-treated rats, the expression of synapsin I mRNA was significantly reduced; interestingly, the neonatal treatment with 6-hydroxydopamine normalized its expression. Therefore, brain-reactive neurochemical changes triggered by 6-hydroxydopamine were suppressed by perinatal morphine exposure whereas the association of morphine exposure and 6-hydroxydopamine lesion promoted the normal mRNA expression of the synaptic marker synapsin I.

Adrenergic Agents↗

PubMed1993

Chronic continuous and intermittent L-3,4-dihydroxyphenylalanine treatments differentially affect basal ganglia function in 6-hydroxydopamine lesioned rats--an autoradiographic study using [3H]flunitrazepam.

The effects of chronic 'continuous' and 'intermittent' L-3,4-dihydroxyphenylalanine treatments on GABA receptor function in the basal ganglia of rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle was investigated, by autoradiography with [3H]flunitrazepam. The 6-hydroxydopamine lesion itself, increased [3H]flunitrazepam binding in the substantia nigra pars reticulata (+17%, with respect to intact side) and entopeduncular nucleus (+44%), but decreased binding in the globus pallidus of the denervated hemisphere (-20%). 'Intermittent' L-3,4-dihydroxyphenylalanine treatment reduced the [3H]flunitrazepam binding changes observed in the substantia nigra pars reticulata (-13%) and entopeduncular nucleus (-4%), whereas 'continuous' infusion of the same daily dose of L-3,4-dihydroxyphenylalanine had less effect (+14%, substantia nigra pars reticulata; +26%, entopeduncular nucleus). In contrast, the [3H]flunitrazepam binding decrease in the globus pallidus of the 6-hydroxydopamine lesioned animals was unaffected by either regime of chronic L-3,4-dihydroxyphenylalanine treatment. The changes in GABA receptor function implied by these results provide further insight into the pathophysiological effects of L-3,4-dihydroxyphenylalanine treatment on basal ganglia function, following dopamine denervation. In accordance with existing electrophysiological and biochemical evidence on this subject, the main implications of these results include reduced GABA sensitivity of neurons in the entopeduncular nucleus and substantia nigra pars reticulata, following chronic 'intermittent', but not chronic 'continuous' L-3,4-dihydroxyphenylalanine treatment; this may be due to a reversal of the 6-hydroxydopamine induced decrease in the GABA-mediated neurotransmission in the striatoentopeduncular and striatonigral pathways. In contrast, the regulation of GABA receptors in the globus pallidus does not appear to be subject to modulation by chronic L-3,4-dihydroxyphenylalanine administration, suggesting that dopamine replacement in this manner does not modify the 6-hydroxydopamine induced increase in GABA-mediated neurotransmission in the stratopallidal pathway.

Animals↗

PubMed1995

Neonatal 6-hydroxydopamine lesions lead to opposing changes in the levels of dopamine receptors and their messenger RNAs.

Previous studies have established that selective damage to the early-developing components of the mesostriatal dopamine system produces profound changes in dopamine D1 receptor-mediated behaviors, while decreasing D1 receptor density. In order to better understand the effects of early intrastriatal 6-hydroxydopamine lesions, we studied the ontogenetic expression (postnatal days 7, 14, 35 and 90) of D1 and D2 receptors, and their corresponding messenger RNAs, in rats that had received intrastriatal 6-hydroxydopamine or vehicle lesions on postnatal day 1. Using receptor autoradiography, significant (P < 0.05) decreases in [3H]SCH 23390 binding to D1 receptors in the rostral and caudal dorsomedial and ventromedial caudate of 6-hydroxydopamine-lesioned animals were evident by postnatal day 7, and remained depressed at all future time points. A significant decrease in D1 receptor concentration occurred in the dorsolateral caudate at later time points (postnatal days 35 and 90). [3H]Spiperone binding to D2 receptor sites was unchanged throughout the entire study. In situ hybridization for D1 and D2 messenger RNA expression showed contrasting results. 6-Hydroxydopamine induced significant decreases of D1 messenger RNA levels in the dorsolateral and dorsomedial caudate by postnatal day 7. By postnatal day 14, messenger RNA expression was significantly elevated in the dorsomedial and ventromedial caudate of the 6-hydroxydopamine group, and remained elevated thereafter. D1 messenger RNA levels became elevated in the lateral caudate at later time points (postnatal days 35 and 90). The opposing changes in D1 receptor concentrations and the messenger RNA encoding the protein did not occur as a consequence of increased transport of D1 receptors to striatonigral terminals. D2 messenger RNA levels in the dorsal caudate were significantly decreased on postnatal day 7, and became higher than controls at postnatal day 14, but were unchanged from controls at later time points. Together, the D1 receptor and D1 messenger RNA findings suggest that the normal relationship between levels of D1 receptor transcript and D1 receptor protein is permanently altered following the early loss of dopamine. In contrast, the results indicate that dopamine plays a minor role in the early postnatal development of the D2 receptor protein and transcript. These findings suggest that dopamine may be involved in the coordinated expression of some dopamine receptors and their corresponding messenger RNAs during development.

Aging↗

PubMed1996

Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by instrastriatal 6-hydroxydopamine in the rat.

6-Hydroxydopamine-induced nerve terminal lesion of the nigrostriatal system may provide a partial lesion model of Parkinson's disease useful for the assessment of neuroprotective treatments and behavioral recovery after therapeutic intervention. The aim of the present study was to assess the retrograde degenerative changes in the dopaminergic neurons of the substantia nigra and the associated behavioral and neurochemical consequences of intrastriatal injections of 6-hydroxydopamine in young adult rats. Four groups of rats were stereotaxically injected in the right striatum with graded doses of 6-hydroxydopamine ranging from 0 to 20 mu g. Structural and functional deficits were quantified by tyrosine hydroxylase-immunoreactive nigral cell numbers, striatal dopamine content, skilled paw use, and drug-induced rotation. The results show that striatal 6-hydroxydopamine lesions produce dose-dependent decreases in striatal dopamine levels and tyrosine hydroxylase-immunoreactive cell numbers in the ipsilateral substantia nigra, accompanied by a significant long-lasting atrophy of the remaining dopaminergic neurons. Paw reaching test scores on the side contralateral to the lesion were non-linearly correlated with dopaminergic neuronal cell loss and exhibited a clear symptomatic threshold such that impaired paw use appeared only after >50% loss of nigral dopamine neurons or a reduction of 60-80% of striatal dopamine levels. The behavioral, cellular, and neurochemical effects of the nerve terminal lesion thus bear some resemblance to the early stages of Parkinson's disease, where the severity of motor impairment is correlated with the loss of dopamine in the striatum and dopaminergic neuronal loss in the substantia nigra. Rats with intrastriatal 6-hydroxydopamine lesions thus provide a model of progressive dopamine neuron degeneration useful not only for the exploration of neuroprotective therapeutic intervention but also for the study of mechanisms of functional and structural recovery after subtotal damage of the nigrostriatal dopamine system.

Animals↗

PubMedDate not supplied

Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson's disease.

Cannabinoids have been reported to provide neuroprotection in acute and chronic neurodegeneration. In this study, we examined whether they are also effective against the toxicity caused by 6-hydroxydopamine, both in vivo and in vitro, which may be relevant to Parkinson's disease (PD). First, we evaluated whether the administration of cannabinoids in vivo reduces the neurodegeneration produced by a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. As expected, 2 weeks after the application of this toxin, a significant depletion of dopamine contents and a reduction of tyrosine hydroxylase activity in the lesioned striatum were noted, and were accompanied by a reduction in tyrosine hydroxylase-mRNA levels in the substantia nigra. None of these events occurred in the contralateral structures. Daily administration of delta9-tetrahydrocannabinol (delta9-THC) during these 2 weeks produced a significant waning in the magnitude of these reductions, whereas it failed to affect dopaminergic parameters in the contralateral structures. This effect of delta9-THC appeared to be irreversible since interruption of the daily administration of this cannabinoid after the 2-week period did not lead to the re-initiation of the 6-hydroxydopamine-induced neurodegeneration. In addition, the fact that the same neuroprotective effect was also produced by cannabidiol (CBD), another plant-derived cannabinoid with negligible affinity for cannabinoid CB1 receptors, suggests that the antioxidant properties of both compounds, which are cannabinoid receptor-independent, might be involved in these in vivo effects, although an alternative might be that the neuroprotection exerted by both compounds might be due to their anti-inflammatory potential. As a second objective, we examined whether cannabinoids also provide neuroprotection against the in vitro toxicity of 6-hydroxydopamine. We found that the non-selective cannabinoid agonist HU-210 increased cell survival in cultures of mouse cerebellar granule cells exposed to this toxin. However, this effect was significantly lesser when the cannabinoid was directly added to neuronal cultures than when these cultures were exposed to conditioned medium obtained from mixed glial cell cultures treated with HU-210, suggesting that the cannabinoid exerted its major protective effect by regulating glial influence to neurons. In summary, our results support the view of a potential neuroprotective action of cannabinoids against the in vivo and in vitro toxicity of 6-hydroxydopamine, which might be relevant for PD. Our data indicated that these neuroprotective effects might be due, among others, to the antioxidant properties of certain plant-derived cannabinoids, or exerted through the capability of cannabinoid agonists to modulate glial function, or produced by a combination of both mechanisms.

Animals↗

PubMed2006

Angiotensin type-1-receptor antagonists reduce 6-hydroxydopamine toxicity for dopaminergic neurons.

Angiotensin II activates (via type 1 receptors) NAD(P)H-dependent oxidases, which are a major source of superoxide, and is relevant in the pathogenesis of several cardiovascular diseases and certain degenerative changes associated with ageing. Given that there is a brain renin-angiotensin system and that oxidative stress is a key contributor to Parkinson's disease, we investigated the effects of angiotensin II and angiotensin type 1 (AT(1)) receptor antagonists in the 6-hydroxydopamine model of Parkinson's disease. Rats subjected to intraventricular injection of 6-hydroxydopamine showed bilateral reduction in the number of dopaminergic neurons and terminals. Injection of angiotensin alone did not induce any significant effect. However, angiotensin increased the toxic effect of 6-hydroxydopamine. Rats treated with the AT(1) receptor antagonist ZD 7155 and then 6-hydroxydopamine (with or without exogenous administration of angiotensin) showed a significant reduction in 6-hydroxydopamine-induced oxidative stress (lipid peroxidation and protein oxidation) and dopaminergic degeneration. Dopaminergic degeneration was also reduced by the NAD(P)H inhibitor apocynin. Angiotensin may play a pivotal role, via AT(1) receptors, in increasing the oxidative damage of dopaminergic cells, and treatment with AT(1) antagonists may reduce the progression of Parkinson's disease.

Adrenergic Agents↗

PubMed2001

Inhibition of 6-hydroxydopamine-induced p53 expression and survival of neuroblastoma cells following interaction with astrocytes.

The neurotoxin 6-hydroxydopamine has been used to induce selective dopaminergic cell death in animal models of Parkinson's disease. The response of neurons to this toxin has been shown to be greatly influenced by astrocytes. Our laboratory reported previously that human neuroblastoma SH-SY5Y cells became more resistant to the toxicity of 6-hydroxydopamine when co-cultured with mouse astrocytes. This enhanced tolerance required direct and specific adhesion between SH-SY5Y cells and astrocytes. We hypothesized that this interaction led to biochemical changes in SH-SY5Y cells, thereby protecting these cells from toxicity. To study these changes, we again co-cultured SH-SY5Y cells with astrocytes and treated them with 6-hydroxydopamine. An optimized condition of trypsin treatment was employed to separate SH-SY5Y cells from astrocytes quickly. Western blot analysis demonstrated that 6-hydroxydopamine significantly increased p53 protein in monolayer SH-SY5Y cells grown in either regular medium or conditioned medium from astrocytes. This change, however, was not observed in the group co-cultured with astrocytes. Data obtained from the ribonuclease protection assay indicated that similar changes also occurred at the transcriptional level. The enhanced resistance of the co-cultured SH-SY5Y cells to the toxicity of 6-hydroxydopamine is attributed to the ability of astrocytes to prevent the increase of p53 induced by this toxin. This study demonstrates the significance of the interaction between astrocytes and neurons when they are exposed to neurotoxins.

Animals↗

PubMed1997

Apomorphine priming alters the response of striatal outflow pathways to D2 agonist stimulation in 6-hydroxydopamine-lesioned rats.

Chronic treatment with dopaminergic agonists is associated with response fluctuations to L-dihydroxyphenylalanine in Parkinson's disease and enhanced motor activity to D1 and D2 dopamine agonists in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway. In dopamine-depleted rodents this phenomenon has been referred to as "priming" or reverse tolerance. The neurochemical changes that underlie "priming" of dopaminergic agonist responses are poorly understood. Some aspects of priming of D1 agonist-mediated rotation in the 6-hydroxydopamine-lesioned rat have been characterized, but priming of D2-agonist-dependent motor responses has been less thoroughly studied. In this study, examination of rotational behaviour and induction of Fos-like immunoreactivity were used to investigate changes in the striatal outflow systems in response to treatment with the D2 agonist quinpirole in 6-hydroxydopamine-lesioned rats that had been primed with apomorphine. Administration of apomorphine (0.5 mg/kg; three injections at three to six day intervals) permitted an otherwise inactive dose of quinpirole (0.25 mg/kg) to produce robust contralateral rotation and to induce the expression of Fos in striatal neurons belonging to the striato-nigro-entopeduncular ("direct") pathway. The increase in contralateral rotation and ipsilateral striatal Fos expression following administration of quinpirole to apomorphine-primed rats was mediated by a D2-like receptor and did not appear to be due to a change in sensitivity of D2 receptors. Apomorphine priming also enhanced the ability of quinpirole to induce Fos expression in the globus pallidus, a target of the striatopallidal ("indirect") pathway. Western blot analysis confirmed that treatment with quinpirole induced the expression of c-Fos protein with no change in the expression of 35-37,000 mol. wt Fos-related antigens in apomorphine-primed rats treated with water or quinpirole. Induction of Fos expression in the striatum generally results from blockade of D2 receptors and the striato-nigro-entopeduncular pathway preferentially expresses D1 receptors. Thus, the quinpirole-dependent induction of striatal Fos in apomorphine-primed 6-hydroxydopamine-lesioned rats represents a qualitative alteration in striatal outflow. These studies demonstrate that pretreatment of 6-hydroxydopamine-lesioned rats with apomorphine increases the activity of the "direct" and "indirect" striatal outflow pathways in response to D2 receptor stimulation. These changes have the net result of enhancing thalamocortical activity and likely underlie the enhanced contralateral rotation produced by quinpirole in apomorphine-primed rats. Changes in striatal outflow, particularly in the striato-nigro-entopeduncular pathway, may contribute to alterations in D2-dependent motor responses observed after chronic dopaminergic stimulation in the dopamine-depleted striatum.

Animals↗

PubMed1997

Glial cell line-derived neurotrophic factor attenuates behavioural deficits and regulates nigrostriatal dopaminergic and peptidergic markers in 6-hydroxydopamine-lesioned adult rats: comparison of intraventricular and intranigral delivery.

The effects of intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor were tested on low dose (0.05 mg/kg) apomorphine-induced rotations and tyrosine hydroxylase activity in the substantia nigra and striatum of stable 6-hydroxydopamine-lesioned rats. In addition, we determined if 6-hydroxydopamine lesions in the absence or presence of treatment affected neuropeptide (substance P, met-enkephalin, dynorphin) content in the striatum. Glial cell line-derived neurotrophic factor, when administered intranigrally, prevented apomorphine-induced rotational behaviour for 11 weeks following a single injection. In comparison, intraventricularly-administered glial cell line-derived neurotrophic factor produced a transient reduction in rotational behaviour that lasted for two to three weeks following a single injection. We also show that rotational behaviour is reduced following each subsequent intraventricular injection of glial cell line-derived neurotrophic factor given every six weeks, a time-point when baseline rotation deficits were re-established. Intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor significantly reduced weight gain in all 6-hydroxydopamine-lesioned rats in this study. Following behavioural analysis where a confirmed improvement of behaviour was established, tissues were dissected for neurochemical analysis. In lesioned rats with intranigral injections of administered glial cell line-derived neurotrophic factor, significant increases of nigral, but not striatal tyrosine hydroxylase activity were measured. Additionally, 6-hydroxydopamine lesions significantly increased striatal dynorphin (61-139%) and met-enkephalin (81-139%), but not substance P levels. In these rats, intranigrally-administered glial cell line-derived neurotrophic factor injections reversed lesion-induced increases in nigral dynorphin A levels and increased nigral dopamine levels, but did not alter nigral met-enkephalin or substance P levels nor striatal dopamine levels. In lesioned rats with intraventricular injections of glial cell line-derived neurotrophic factor, tyrosine hydroxylase ispilateral to the lesion was increased in the substantia nigra, but not in the striatum. Intraventricularly-administered glial cell line-derived neurotrophic factor did not reverse lesion-induced increases in nigral dynorphin A or met-enkephalin levels nor did glial cell line-derived neurotrophic factor affect substance P levels in the striatum. These results suggest that in an animal model of Parkinson's disease, the neurotrophic factor glial cell line-derived neurotrophic factor reverses behavioural consequences of 6-hydroxydopamine administration, an effect that may involve both dopaminergic and peptidergic neurotransmission.

Animals↗

PubMed2001

Complexities in the neurotoxic actions of 6-hydroxydopamine in relation to the cytoprotective properties of taurine.

The neurotoxin 6-hydroxydopamine was shown to cause an imbalance between the direct and indirect pathways of the striato-nigral system as evidenced by a decreased release of gamma-aminobutyric acid and taurine in the substantia nigra but not in the globus pallidus following neostriatal stimulation with kainate (100 microM). The neurotoxicity of 6-hydroxydopamine is generally believed to result from reactive-oxygen radical formation, although it is also known to inhibit mitochondrial NADH dehydrogenase. The release of Fe(II) from the unactivated form [3Fe(III)-4S] of cytoplasmic aconitase (EC(50) < 8 microM) was shown to be followed by the slower oxidation of thiol groups in the protein. Complete loss of -SH groups, and enzyme activity, was seen after incubation of glyceraldenyde-3-phosphate dehydrogenase with 200 microM 6-hydroxydopamine for 75 min at 37 degrees C (IC(50) = 70.8 +/- 0.3 microM). Thus the cellular effects of 6-hydroxydopamine are complex, involving impairment of mitochondrial function, iron- release, sulphydryl-group oxidation, and enzyme inhibition in addition to direct generation of reactive oxygen radicals. Taurine, which is known to be neuroprotective in some other systems, only affords protection against some of these effects, thereby explaining its reported ineffectiveness against 6-hydroxydopamine toxicity.

Aconitate Hydratase↗

PubMed1996

Nature of inhibition of mitochondrial respiratory complex I by 6-Hydroxydopamine.

The catecholaminergic neurotoxin 6-hydroxydopamine causes parkinsonian symptoms in animals and it has been proposed that reactive oxygen species and oxidative stress, enhanced by iron, may play a key role in its toxicity. The present results demonstrate that 6-hydroxydopamine reversibly inhibits complex I (NADH dehydrogenase) of brain mitochondrial respiratory chain in isolated mitochondria. 6-Hydroxydopamine itself, rather than its oxidative products, was responsible for the inhibition. Iron (III) did not enhance inhibition but decreased it by stimulating the nonenzyme oxidation of 6-hydroxydopamine. Inhibition was potentiated to some extent by calcium ion. Desferrioxamine protected complex I activity against the inhibition, but it was not due to its chelator or antioxidative properties. Desferrioxamine was also shown to activate NADH dehydrogenase in the absence of 6-hydroxydopamine. Activation of mitochondrial respiration by desferrioxamine may contribute to the enhanced neuron survival in the presence of desferrioxamine in some neurodegenerative conditions.

Animals↗