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Biomedical subjects

P Jenner

Publications and source records attributed to P Jenner.

At least 127 records · Page 7Linked to original sources
PubMed1996

Mitochondrial respiratory enzyme function and superoxide dismutase activity following brain glutathione depletion in the rat.

In substantia nigra from patients with Parkinson's disease, there are decreased levels of reduced glutathione (GSH) and diminished activities of mitochondrial complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH), along with increased activity of superoxide dismutase (SOD). However, the interrelationship among these events is uncertain. We now report the effect of decreased brain GSH levels on SOD and mitochondrial respiratory enzyme activity in rat brain. In addition, we have investigated the ability of thioctic acid, an endogenous antioxidant, to alter these parameters. Unilateral or bilateral intracerebroventricular (ICV) administration of buthionine sulphoximine (BSO; 1 x 3.2 mg or 2 x 1.6 mg) over a 48-hr period reduced cortical GSH by 55-70%. There was no change in the activity of complex I, II/III, or IV or of citrate synthase in cortex. Similarly, there was no alteration of mitochondrial or cytosolic SOD activity. Thioctic acid (50 or 100 mg/kg IP) alone had no effect on cortical GSH levels in control animals and did not reverse the decrease in GSH levels produced by unilateral or bilateral ICV BSO administration. Thioctic acid (50 or 100 mg/kg IP) had no overall effect on complex I, II/III, or IV or on citrate synthase activity in control animals. Thioctic acid also did not alter cortical mitochondrial respiratory enzyme activity in BSO-treated rats. At the lower dose, thioctic acid tended to increase mitochondrial and cytosolic SOD activity in control animals and in BSO-treated rats. However, at the higher dose, thioctic acid tended to decrease mitochondrial SOD activity. Overall, there was no consistent effect of thioctic acid (50 or 100 mg/kg IP) on SOD activity in control or BSO-treated animals. This study shows that BSO-induced glutathione deficiency does not lead to alterations in mitochondrial respiratory enzyme activity or to changes in SOD activity. GSH depletion in Parkinson's disease therefore may not account for the alterations occurring in complex I and mitochondrial SOD in substantia nigra. Thioctic acid did not alter brain GSH levels or mitochondrial function. Interestingly, however, it did produce some alterations in SOD activity, which may reflect either its antioxidant activity or its ability to act as a thiol-disulphide redox couple.

Animals↗
PubMed1996

D3 receptor expression within the basal ganglia is not affected by Parkinson's disease.

Quantitative receptor autoradiography and in situ hybridization were used to investigate the expression of dopamine D3 receptors in sections of human brain containing limbic (nucleus accumbens) and striatal (caudate nucleus, putamen) regions. High levels of dopamine D3 receptor mRNA and specific [3H](+/-)7-hydroxy-N,N-di-N-propyl-2-aminotetralin ([3H]7-OH-DPAT) binding sites were detected in the nucleus accumbens with lower levels in the caudate nucleus and putamen. No difference in D3 receptor expression was observed between normal and parkinsonian brain. These results indicate that D3 receptor expression is not altered in Parkinson's disease. In addition, they suggest that dopamine release in striatal and limbic areas is not necessary for maintenance of D3 receptor expression.

Aged↗
PubMed1996

Inhibition of [3H]dopamine uptake into striatal synaptosomes by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be endogenous neurotoxins causing nigral cell death in Parkinson's disease. These compounds inhibit mitochondrial function but, like MPP+, require accumulation in dopaminergic neurones via the dopamine reuptake system to exert toxicity. We, now, examine the substrate affinity of 14 neutral and quaternary isoquinoline derivatives (7 isoquinolines, 2 dihydroisoquinolines and 5 1,2,3,4-tetrahydroisoquinolines) for the dopamine reuptake system by their ability to inhibit the uptake of [3H]dopamine into rat striatal synaptosomes. Ten isoquinoline derivatives and MPP+ inhibited [3H]dopamine uptake in a concentration-dependent manner. Only 5 isoquinoline derivatives produced 50% inhibition of [3H]dopamine uptake (IC50 = 8.0-50.0 microM), none of which were as potent as MPP+ (IC50 = 0.33 microM). These findings suggest that isoquinoline derivatives are moderate to poor substrates for the dopamine reuptake system and that high concentrations of, or prolonged exposure to, isoquinoline derivatives may be necessary to cause neurodegeneration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Oxidative stress and Parkinson's disease.

The underlying mechanism of cell death in substantia nigra of Parkinson's disease patients remains unknown. Biochemical changes occurring in substantia nigra in Parkinson's disease (increased iron levels, inhibition of complex I activity and decreased reduced glutathione levels; GSH) suggest that oxidative stress and free radical species may be involved. In particular, a decrease in GSH levels may be an early component of the process, since this also occurs in incidental Lewy body disease (presymptomatic Parkinson's disease). GSH is lost only from the substantia nigra in Parkinson's disease and this does not occur in other neurodegenerative disorders of the basal ganglia. GSH loss appears to be global throughout the substantia nigra and not localized to either the glia or neuronal elements. The activity of enzymes involved in the glutathione cycle are normal with the exception of gamma-glutamyltranspeptidase, the activity of which is increased. This could result in increased removal and degradation of glutathione from cells. Depletion of GSH in rat using L-buthionine-[S, R]-sulfoxamine (BSO) potentiates 6-hydroxydopamine (6-OHDA) toxicity but does not in itself produce degeneration of the nigrostriatal pathway. Oxidative stress may be a potentially important factor in the degeneration of the substantia nigra in Parkinson's disease and warrants further investigation into its role in this process.

Animals↗
PubMed1996

Effects of isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mitochondrial respiration.

Isoquinoline derivatives exert 1-methyl-4-phenylpyridinium (MPP+)-like activity as inhibitors of complex I and alpha-ketoglutarate dehydrogenase activity in rat brain mitochondrial fragments. We now examine the ability of 19 isoquinoline derivatives and MPP+ to accumulate and inhibit respiration in intact rat liver mitochondria, assessed using polarographic techniques. None of the compounds examined inhibited respiration supported by either succinate + rotenone or tetramethylparaphenylenediamine (TMPD) + ascorbate. However, with glutamate + malate as substrates, 15 isoquinoline derivatives and MPP+ inhibited state 3 and, to a lesser extent, state 4 respiration in a time-dependent manner. None of the isoquinoline derivatives were more potent than MPP+. 6,7-Dimethoxy-1-styryl-3,4-dihydroisoquinoline uncoupled mitochondrial respiration. Qualitative structure-activity relationship studies revealed that isoquinolinium cations were more active than isoquinolines in inhibiting mitochondrial respiration; these, in turn, were more active than dihydroisoquinolines and 1,2,3,4-tetrahydroisoquinolines. Three-dimensional quantitative structure-activity relationship studies using Comparative Molecular Field Analysis showed that the inhibitory potency of isoquinoline derivatives was determined by steric, rather than electrostatic, properties of the compounds. A hypothetical binding site was identified that may be related to a rate-limiting transport process, rather than to enzyme inhibition. In conclusion, isoquinoline derivatives are less potent in inhibiting respiration in intact mitochondria than impairing complex I activity in mitochondrial fragments. This suggests that isoquinoline derivatives are not accumulated by mitochondria as avidly as MPP+. The activity of charged and neutral isoquinoline derivatives implicates both active and passive processes by which these compounds enter mitochondria, although the quaternary nitrogen moiety of the isoquinolinium cations favours mitochondrial accumulation and inhibition of respiration. These findings suggest that isoquinoline derivatives may exert mitochondrial toxicity in vivo similar to that of MPTP/MPP+.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

The isomers of thioctic acid alter C-deoxyglucose incorporation in rat basal ganglia.

Nigral cell death in Parkinson's disease is associated with decreased reduced glutathione (GSH) levels, impaired complex I activity and inhibition of alpha-ketoglutarate dehydrogenase (alpha-KGDH) in substantia nigra. Thioctic acid exerts antioxidant activity through a thiol-disulphide redox couple and is an essential cofactor for alpha-KGDH. However, it is not known whether or not thioctic acid enters basal ganglia or exerts beneficial effects in Parkinson's disease. As a global measure of altered cerebral function, the effect of R- and S-thioctic acid on 14C-2-deoxyglucose (14C-2DG) incorporation was investigated in rats. Rats were treated with either R- or S-thioctic acid (50 mg/kg IP) or 0.9% saline acutely or for 5 days and 14C-2DG incorporation in basal ganglia was assessed. Following acute administration, R- but not S-thioctic acid caused an overall increase in 14C-2DG incorporation that was significant in both substantia nigra zona compacta and zona reticulata. R-thioctic acid also increased the incorporation of 14C-2DG in the medial forebrain bundle, thalamus, and red nucleus. S-thioctic acid decreased 14C-2DG incorporation in the subthalamic nucleus, but increased it in the red nucleus. Following repeated administration, R-thioctic acid no longer increased 14C-2DG incorporation in either zona compacta or zona reticulata of substantia nigra. However, both R- and S-thioctic acid now decreased 14C-2DG incorporation in the subthalamic nucleus. The data suggest that thioctic acid does enter the brain can alter neuronal activity in areas of the basal ganglia intimately associated with the motor deficits exhibited in Parkinson's disease.

Animals↗
PubMed1996

Toxicity to PC12 cells of isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium (MPP+) are inhibitors of mitochondrial function and substrates for the dopamine re-uptake system, but their neuronal toxicity is unclear. In this study, the effects of exposing PC12 cells to four isoquinoline derivatives (isoquinoline, N-methylisoquinolinium, 6,7-methylenedioxyisoquinoline and 1,2,3,4-tetrahydroisoquinoline) and MPP+ (100-1000 microM) were examined. All compounds exhibited concentration-dependent toxicity as determined by lactate dehydrogenase release, but none of the isoquinoline derivatives were more toxic than MPP+. Cytotoxicity of these compounds appears to be directly correlated with their substrate affinity for the dopamine reuptake system, but not mitochondrial inhibition. Thus, the low toxicity of isoquinoline derivatives towards PC12 cells suggests that high concentrations of or prolonged exposure to these compounds may be necessary to cause the neurodegenerative changes related to Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Dopamine D3 receptors in the basal ganglia of the common marmoset and following MPTP and L-DOPA treatment.

The distribution of the dopamine D3 receptor was studied by receptor autoradiography using [3H]7-OH-DPAT in striatal and extrastriatal brain regions of the common marmoset (Callithrix jacchus). Saturation studies demonstrated that [3H]7-OH-DPAT bound with similar affinity to different regions of marmoset brain. In normal marmosets, specific [3H]7-OH-DPAT binding was found in both striatal and extrastriatal regions. Very high levels of specific [3H]7-OH-DPAT binding were detected in the islands of Calleja and nucleus accumbens but in addition high levels of binding were detected in rostral caudate nucleus and putamen. In common marmosets treated with the selective nigral neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the levels of specific [3H]7-OH-DPAT binding in striatal and extrastriatal regions were not different to those in normal animals. Chronic treatment of MPTP-treated marmosets with L-DOPA/ carbidopa did not alter the levels of specific [3H]7-OH-DPAT binding in any brain region. These results demonstrate that in common marmosets D3 receptors are located in both striatal and limbic regions. The receptor density is not altered by dopaminergic denervation or by chronic L-DOPA administration. The D3 receptor may, therefore, be important in both the therapeutic and adverse effects of drugs used to treat Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Intraventricular infusion of basic fibroblast growth factor (bFGF) in the MPTP-treated common marmoset.

Basic fibroblast growth factor (bFGF) prevents damage to the nigrostriatal system in rodents. We now report the effects of bFGF administered by intraventricular infusion to adult common marmosets (Callithrix jacchus) previously rendered parkinsonian by the administration of 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Infusion commenced 10 weeks after MPTP treatment and the animals received bFGF in low (1.8 micrograms/l), medium (18 micrograms/l), or high (180 micrograms/l) doses over a 28-day period. At weekly intervals, automated activity measurements, behavioral disability scoring, and videotape analyses were made. There was no improvement in the motor deficits exhibited by MPTP-treated common marmosets receiving bFGF infusion compared to vehicle-treated controls. Three of five high dose animals showed neurological impairment prior to the end of the study. No significant differences were found between control and bFGF-infused MPTP-treated common marmosets with respect to nigral tyrosine hydroxylase immunoreactive cell counts and striatal [3H]mazindol binding. All high dose animals showed hydrocephalus which was also observed in four other animals receiving bFGF. Histological examination revealed proliferation of the choroid plexus and ependyma which was most marked in the high dose animals. Adverse effects, in the form of hydrocephalus and neurological deterioration, were presumably secondary to an ependymal and choroid plexus reaction induced by bFGF.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Partial reversal of increased preproenkephalin messenger ribonucleic acid (mRNA) and decreased preprotachykinin mRNA by foetal dopamine cells in unilateral 6-hydroxydopamine-lesioned rat striatum parallels functional recovery.

In situ hybridization histochemistry was used to investigate the expression of striatal preproenkephalin and preprotachykinin messenger ribonucleic acid (mRNA) in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway followed 4 weeks later by implantation of foetal dopamine cells into the denervated striatum. Striatal dopamine deafferentation caused an (+)-amphetamine-induced rotational asymmetry, an increase in striatal preproenkephalin mRNA message, and a decrease in striatal preprotachykinin mRNA message relative to control animals. Two months after grafting a foetal ventral mesencephalon suspension, there was reversal of the rotational asymmetry to (+)-amphetamine. At this time the increase in striatal preproenkephalin mRNA was significantly attenuated and the decrease in preprotachykinin mRNA was partially reversed compared to animals with a 6-hydroxydopamine lesion alone. Subregional analysis showed the attenuation of the increase in preproenkephalin mRNA to occur in dorsolateral, dorsomedial and ventromedial, but not ventrolateral, striatal subdivisions. The partial reversal of the decreased preprotachykinin mRNA density after grafting was only statistically significant in the DM and VM subdivisions. These results demonstrate graft-induced partial recovery of striatal function, as judged by preproenkephalin and preprotachykinin mRNA levels, within 2 months of transplantation.

Animals↗
PubMed1996

An appraisal of the antiparkinsonian activity of piribedil in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets.

The D2 dopamine agonist piribedil is not widely used in the treatment of Parkinson's disease because it was thought to be effective mainly on parkinsonian tremor and to produce a high incidence of peripheral side effects, particular nausea. In this study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates to reevaluate the antiparkinsonian ability of piribedil after its oral administration in the presence or absence of domperidone pretreatment. Adult common marmosets (Callithrix jacchus) were treated with the nigral toxin MPTP to induce a parkinsonian syndrome characterised primarily by bradykinesia and other motor deficits. Oral administration of a solution of piribedil [1-(3,4-methylenedioxybenzyl)-4-(2-pyrimidinyl)piperazine] produced a dose-related reversal of all MPTP locomotor and behavioural deficits. However, this effect was short lived and associated with unwanted effects, particular nausea and retching, which clearly hindered locomotion. In contrast, after pretreatment with the peripheral dopamine antagonist domperidone, administration of piribedil did not induce nausea or retching in MPTP-treated marmosets. In these animals, piribedil caused a more marked and longer lasting enhancement of locomotor activity and a further reduction in behavioural deficits than that observed after administration of piribedil alone. In addition, piribedil induced increased vigilance and awareness. These data show that piribedil can reverse akinesia and rigidity in MPTP-treated primates. In addition, they show the drug to be effective without peripheral side effects when used in conjunction with domperidone. These data indicate that piribedil should be an effective monotherapy for Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Reversal of behavioural abnormalities by fetal allografts in a novel rat model of striatonigral degeneration.

We have developed a rodent model of striatonigral degeneration, one of the core pathologies underlying the disease multiple system atrophy (MSA). 6-Hydroxydopamine (6-OHDA) was administered into the left medial forebrain bundle of male Wistar rats, followed 3-4 weeks later by intrastriatal injection of quinolinic acid into the ipsilateral striatum. The 6-OHDA lesion resulted in ipsilateral rotation to (+)-amphetamine and contralateral rotation to apomorphine. Following the subsequent striatal lesion, amphetamine-induced ipsilateral rotation persisted, but apomorphine-induced contralateral rotation was reduced or abolished. Subsequently, the lesioned striatum was implanted with fetal CNS allografts consisting of cell suspensions derived from striatal primordium alone or combined with cografts of ventral mesencephalon. Cografted rats showed a reduction or reversal of amphetamine-induced rotation. This was not observed in animals receiving striatal grafts alone. Apomorphine-induced contralateral rotation was restored after striatal grafts alone, but only partially in animals receiving sham or cografts. Tyrosine hydroxylase (TH) and dopamine- and cyclic adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP 32) immunocytochemistry showed mesencephalic and striatal graft survival in most animals. However, dopaminergic outgrowth was restricted to the graft deposit. The latter was surrounded by a markedly gliotic glial fibrillary acidic protein-positive capsule continuous with corpus callosum. Dopaminergic reinnervation of denervated and lesioned adult striatum itself was absent, suggesting that rotational recovery was due to diffuse dopamine release. The study shows that combined unilateral lesioning of rodent medial forebrain bundle and striatum results in a characteristic drug-induced rotational response that can be partly restored by mesencephalic/striatal cografts.

Amphetamines↗
PubMed1996

Altered motor function and graft survival produced by basic fibroblast growth factor in rats with 6-OHDA lesions and fetal ventral mesencephalic grafts are associated with glial proliferation.

Basic fibroblast growth factor (bFGF) promotes the survival and growth of dopaminergic neurons. We have investigated the effect of treating fetal ventral mesencephalon with bFGF or nerve growth factor (NGF) on the subsequent survival and function of grafted dopaminergic neurons implanted into the striatum of rats with a unilateral 6-hydroxydopamine lesion. Animals implanted with fetal ventral mesencephalon mixed with bFGF, but not with NGF, displayed more rapid compensation in motor behavior up to 9 weeks after graft implantation. bFGF, but not NGF, produced an increase in the number of tyrosine hydroxylase (TH)-positive neurons, a larger graft volume, and longer neurite outgrowth in comparison to control grafts. bFGF also increased the number of glial fibrillary acidic protein (GFAP)-positive astrocytes within the grafts. The increased number of GFAP-positive astrocytes induced by bFGF correlated with the increase in the number of TR-positive neurons, with graft volume and with neurite outgrowth. These findings support the use of bFGF to promote the functional integration of fetal ventral mesencephalon grafts into the denervated host brain and and suggest that its action may be indirectly mediated through glial cells.

Animals↗
PubMed1996

Repeated administration of escalating high doses of dexfenfluramine does not produce morphological evidence for neurotoxicity in the cortex of rats.

Rats were treated for 28 days with increasing doses of dexfenfluramine (0.5, 1, 1.5, 2, 3, 4 and 5 mg/kg bid ip, each dose given for 4 days before being increased) and subsequently studied at intervals between 1 and 60 days following the cessation of treatment. Control rats received vehicle and were allowed food ad libitum or were pair fed with dexfenfluramine-treated animals. Immediately following drug treatment 5-HT immunoreactivity was increased in cortical areas compared to control animals. Subsequently, there was a persistent decrease in fine fibre density and the appearance of coarse truncated fibres. 5-HT levels in cortex were decreased 1 day following dexfenfluramine treatment but recovered to control values by 15 days. GFAP and GAP 43 immunoreactivity was unaffected by dexfenfluramine treatment compared to control animals, indicating a lack of evidence for neuronal degeneration and regeneration. Dexfenfluramine treatment decreased the density of 5-HT uptake sites in the cortex, labelled with [3H]-citalopram, but this partially recovered towards control values at 60 days. These alterations in 5-HT terminal networks conflict with the return of 5-HT levels to normal and the lack of evidence for degenerative changes or neuronal regrowth. On the basis of these results, it cannot be concluded that dexfenfluramine is neurotoxic.

Animals↗
PubMed1996

Nigral cell loss produced by infusion of isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium (MPP+) are potential endogenous neurotoxins causing nigral cell death from Parkinson's disease. We now report the effects of 7 days unilateral supranigral infusion in rats of four isoquinoline derivatives, namely N-n-propylisoquinolinium (N-Pr-IQ+), N-methyl-6,7-dimethoxyisoquinolinium (N-Me-6,7-diOMe-IQ+), 6,7-dimethoxy-1-styryl-3,4-dihydroisoquinoline (6,7-diOMe-1-S-3,4-DHIQ) and 1,2,3,4-tetrahydroisoquinoline (THIQ) compared to MPP+. MPP+ (33 nmol/24h)-infused rats showed a marked reduction in motor activity and displayed ipsilateral postural asymmetry. Administration of apomorphine or (+)-amphetamine to these animals produced robust contralateral and ipsilateral rotations, respectively. In contrast, rats infused with the isoquinoline derivatives (150 nmol/24h) did not show spontaneous or drug-induced motor changes. Infusion of MPP+ decreased the number of tyrosine hydroxylase (TH)-positive cells in the ipsilateral substantia nigra pars compacta (SNc) by approximately 90%. Infusion of N-Me-diOme-IQ+ and THIQ produced approximately 42% and 20% ipsilateral SNc cell loss, respectively, but N-Pr-IQ+ and 6,7-diOMe-1-S-3,4-DHIQ did not alter SNc cell numbers. MPP+ markedly depleted the dopamine (DA, 95%), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) content of the ipsilateral striatum. N-Me-diOMe-IQ+ and THIQ also reduced the DA content of the ipsilateral striatum by approximately 39% and 20% respectively, but N-Pr-IQ+ and 6,7-diOme-1-S-3,4-DHIQ did not deplete striatal DA content. The isoquinoline derivatives slightly reduced (N-Me-diOMe-IQ+ and THIQ) or had no effect (N-Pr-IQ+ and 6,7-diOMe-1-S-3,4-DHIQ) on DOPAC or HVA levels. In conclusion, some isoquinoline derivatives that are substrates for the dopamine re-uptake system and inhibitors of mitochondrial function, are toxic to nigral dopaminergic neurones. Chronic exposure to endogenous or exogenous isoquinoline derivatives might contribute to cell death in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Effect of repeated administration of dopamine agonists on striatal neuropeptide mRNA expression in rats with a unilateral nigral 6-hydroxydopamine lesion.

Striatal mRNA expression for preproenkephalin (PPE) and preprotachykinin (PPT) was studied in unilateral 6-OHDA lesioned rats treated subchronically with a range of selective and non-selective D-1 or D-2 dopamine (DA) agonists. Apomorphine (5 mg/kg sc), pergolide (0.5 mg/kg sc), SKF 38393 (5 mg/kg sc), SKF 80723 (1.5 mg/kg sc), and quinpirole (5 mg/kg sc), or 0.9% saline (150 microliters sc) were all given twice daily (except pergolide: once daily) for 7 days. The abundance of PPE mRNA was not altered by any of these DA agonists in the intact striatum contralateral to the 6-OHDA lesion. Only apomorphine and quinpirole increased the abundance of PPT mRNA in the intact striatum. In saline treated 6-OHDA lesioned animals PPE mRNA was elevated (+160%, p < 0.005) and PPT mRNA decreased (-36%, p < 0.005) in the denervated striatum. The up-regulation of striatal PPE mRNA in the lesioned striatum was reversed only by pergolide. The downregulation of striatal PPT mRNA in the lesioned striatum was reversed only by apomorphine. The differential sensitivity of the striatal PPE message to the long-acting DA agonist pergolide, and of the striatal PPT message to the mixed D-1/D-2 DA agonist apomorphine suggests that the striatopallidal enkephalinergic pathways are mainly regulated by prolonged DA receptor stimulation, whereas the striatonigral substance P pathways are mainly regulated by mixed D-1/D-2 DA receptor stimulation.

Animals↗
PubMed1996

Thioctic acid does not restore glutathione levels or protect against the potentiation of 6-hydroxydopamine toxicity induced by glutathione depletion in rat brain.

Decreased reduced glutathione (GSH) levels are an early marker of nigral cell death in Parkinson's disease. Depletion of rat brain GSH by intracerebroventricular administration of buthionine sulphoximine (BSO) potentiates the toxicity of 6-hydroxydopamine (6-OHDA) to the nigrostriatal pathway. We have investigated whether thioctic acid can replenish brain GSH levels following BSO-induced depletion and/or prevent 6-OHDA induced toxicity. Administration of BSO (2 x 1.6 mg i.c.v.) to rats depleted striatal GSH levels by upto 75%. BSO treatment potentiated 6-OHDA (75 micrograms i.c.v.) toxicity as judged by striatal dopamine content and the number of tyrosine hydroxylase immunoreactive cells in substantia nigra. Repeated treatment with thioctic acid (50 or 100 mg/kg i.p.) over 48h had no effect on the 6-OHDA induced loss of dopamine in striatum or nigral tyrosine hydroxylase positive cells in substantia nigra. Also thioctic acid treatment did not reverse the BSO induced depletion of GSH or prevent the potentiation of 6-OHDA neurotoxicity produced by BSO. Thioctic acid (50 mg or 100 mg/kg i.p.) alone or in combination with BSO did not alter striatal dopamine levels but increased dopamine turnover. Striatal 5-HT content was not altered by thioctic acid but 5-HIAA levels were increased. Under conditions of inhibition of GSH synthesis, thioctic acid does not replenish brain GSH levels or protect against 6-OHDA toxicity. At last in this model of Parkinson's disease, thioctic acid does not appear to have a neuroprotective effect.

Animals↗