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D Offen

Publications and source records attributed to D Offen.

At least 37 records · Page 2Linked to original sources
PubMed1999

The involvement of p53 in dopamine-induced apoptosis of cerebellar granule neurons and leukemic cells overexpressing p53.

1. The pathogenesis of the selective degeneration of the dopaminergic neurons in Parkinson's disease is still enigmatic. Recently we have shown that dopamine can induce apoptosis in postmitotic neuronal cells, as well as in other cellular systems, thus suggesting a role for this endogenous neurotransmitter and associated oxidative stress in the neuronal death process. 2. Dopamine has been shown to be capable of inducing DNA damage through its oxidative metabolites. p53 is a transcription factor that has a major role in determining cell fate in response to DNA damage. We therefore examined the possible correlation between dopamine-triggered apoptosis, DNA damage and levels of total phosphorylated p53 protein in cultured mouse cerebellar granule neurons. 3. Marked DNA damage and apoptotic nuclear condensation and fragmentation were detected within several hours of exposure to dopamine. An associated marked threefold increase in p53 phosphorylation was observed within this time window. Using a temperature-sensitive p53 activation system in leukemia LTR6 cells, were found that p53 inactivation dramatically attenuated dopamine toxicity. 4. We therefore conclude that DNA damage and p53 activation may have a role in mediating dopamine-induced apoptosis. Modulation of the p53 system may therefore have a protective role against the toxicity of this endogenous neurotransmitter and associated oxidative stress.

Animals↗
PubMed1998

Transgenic mice expressing human Bcl-2 in their neurons are resistant to 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine neurotoxicity.

The protooncogene bcl-2 inhibits neuronal apoptosis during normal brain development as well as that induced by cytotoxic drugs or growth factor deprivation. We have previously demonstrated that neurons of mice deficient in Bcl-2 are more susceptible to neurotoxins and that the dopamine (DA) level in the striatum after systemic 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) administration was significantly lower than in wild-type mice. In the present study we have used transgenic mice overexpressing human Bcl-2 under the control of neuron-specific enolase promoter (NSE-hbcl-2) to test the effects of the neurotoxins 6-hydroxydopamine (6-OHDA) and MPTP on neuronal survival in these mice. Primary cultures of neocortical neurons from normal and transgenic mice were exposed to these dopaminergic neurotoxins. Addition of 6-OHDA resulted in cell death of essentially all neurons from normal mice. In contrast, in cultures generated from heterozygous NSE-hbcl-2 transgenic mice, only 69% of the cells died while those generated from homozygous transgenic mice were highly resistant and exhibited only 34% cell death. A similar effect was observed with neurons treated with MPP+. Moreover, while the striatal dopamine level after MPTP injections was reduced by 32% in the wild type, the concentration remained unchanged in the NSE-hbcl-2 heterozygous mice. In contrast levels of glutathione-related enzymes were unchanged. In conclusion, overexpression of Bcl-2 in the neurons provided protection, in a dose-dependent manner, against neurotoxins known to selectively damage dopaminergic neurons. This study provides ideas for inhibition of neuronal cell death in neurodegenerative diseases and for the development of efficient neuroprotective gene therapy.

Animals↗
PubMed1998

Levodopa toxicity and apoptosis.

Many in vitro studies have shown that levodopa is a potent toxin which is lethal to various cultured neuronal and non-neuronal cells. The in vitro toxicity of levodopa is linked mainly to its auto-oxidation, which generates a variety of harmful free radical species including superoxide, hydrogen peroxide, and hydroxyl radicals, and also semiquinones and quinones produced via the dopa-melanin metabolic route. Such toxic effects of levodopa can be blocked by co-treatment with antioxidants, particularly thiol-containing compounds. Several studies have shown that levodopa kills cells by triggering apoptosis, an active, intrinsic cell suicide program. Exposure of cultured neurons to levodopa induced the characteristic apoptotic cascade, including cell shrinkage, membrane blebbing, and nuclear and DNA fragmentation. Although levodopa is extremely toxic in vitro, there is no evidence that it damages nigrostriatal dopaminergic neurons in vivo in experimental animals and in patients with Parkinson's disease (PD). Likewise, although there is some evidence for the occurrence of apoptosis in the parkinsonian substantia nigra, it is not known whether levodopa administration is capable of inducing or accelerating programmed cell death of residual pigmented nigral neurons in PD.

Animals↗
PubMed1998

HTLV-1 in mouthwash cells from a TSP/HAM patient and asymptomatic carriers.

Using in situ hybridization, the presence of T-cell lymphotrophic virus type I (HTLV-I) was shown in blood lymphocytes of one tropical spastic paraparesis (TSP/HAM) patient and in two asymptomatic carriers. HTLV-I was also detected in epithelial cells derived from mouthwash of the TSP/HAM patient. Mouthwash of one of the carriers showed an infected lymphocyte while mouthwash of the other carrier was negative. The infected epithelial cells stained both in the nucleus and in the cytoplasm, which indicated the presence of the virus in both subcellular compartments. Our observations suggest that saliva cells, lymphocytes and epithelial cells, may potentially participate in oral transmission of HTLV-I.

Aged↗
PubMed1998

Enhanced oxidative stress and altered antioxidants in brains of Bcl-2-deficient mice.

Bcl-2 is an antiapoptotic protein located in the outer mitochondrial membrane. Cellular perturbations associated with programmed cell death may be the consequence of disrupted mitochondrial function as well as excessive production of reactive oxygen species (ROS). Numerous studies indicate that Bcl-2 is involved in opposing cell death induced by oxidative stimuli, but its mode of action is uncertain. We reexamined the role of Bcl-2 by using a loss-of-function model, Bcl-2 knockout mice. Brains from Bcl-2-deficient mice had a 43% higher content of oxidized proteins and 27% lower number of cells in the cerebellum relative to wild-type mice. Incubation of cerebellar neurons from Bcl-2 +/+ brains with 0.5 mM dopamine caused 25% cell death, whereas in Bcl-2-deficient cells, it resulted in 52% death; glial cells provided protection in both cultures. Splenocytes from Bcl-2-deficient mice were also killed more effectively by dopamine as well as paraquat. Bcl-2-deficient mice did not survive intraperitoneal injection of MPTP, which caused a decrease in dopamine level in the striatum of Bcl-2 +/- brains, which was more significant than in wild-type mice. When compared with Bcl-2 +/+ brains, brains of 8-day-old Bcl-2-deficient mice had higher activities of the antioxidant enzymes GSH reductase (192%) and GSH transferase (142%), whereas at the age of 30 days, GSH peroxidase was significantly lower (66%). Activities of GSH transferase and GSH reductase increased significantly (158 and 262%, respectively) from day 8 to day 30 in Bcl-2 +/+ mice, whereas GSH peroxidase decreased (31%) significantly in Bcl-2 -/- animals. In summary, our results demonstrated enhanced oxidative stress and susceptibility to oxidants as well as altered levels of antioxidant enzymes in brains of Bcl-2-deficient mice. It is concluded that Bcl-2 affects cellular levels of ROS, which may be due to an effect either on their production or on antioxidant pathways.

Animals↗
PubMed1998

Antibodies from ALS patients inhibit dopamine release mediated by L-type calcium channels.

OBJECTIVE: To examine the presence of anti-L-type calcium channel antibodies in the serum of ALS patients. BACKGROUND: Autoimmunity has been hypothesized as one of the mechanisms underlying the pathogenesis of sporadic ALS. Previous studies reported that sera from patients with sporadic ALS contain antibodies against voltage-gated calcium channels (L-type and P-type), but others do not support these findings. METHODS: Regulated secretion of tritiated dopamine ([3H]DA) in PC12 cells is mediated exclusively by calcium entry through L-type calcium channels. To examine whether purified ALS immunoglobulin G (IgG) inhibits [3H]DA release by interfering with calcium entry through L-type calcium channels, evoked release in PC12 cells was determined in the presence of ALS IgG. This functional assay provides a sensitive way to examine L-type calcium channel interaction with IgG from ALS patients. RESULTS: A significant inhibition of depolarization-evoked [3H]DA release (32+/-4%) was observed by purified IgG from ALS patients compared with control subjects (11+/-2%; p < 0.01). Significant inhibition by IgG occurred in 79% (15/19) of the ALS patients compared with only 29% (5/17) in the control group (p < 0.01). The level of calcium channel inhibition by ALS IgG correlated positively with disease duration (r = 0.68; p < 0.01) and correlated negatively with age (r = -0.48; p < 0.05). CONCLUSIONS: These results confirm the presence of antibodies against the L-type calcium channel in the majority of sera from ALS patients, supporting their role in the pathogenesis of ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1997

Levodopa induces apoptosis in cultured neuronal cells--a possible accelerator of nigrostriatal degeneration in Parkinson's disease?

Apoptosis is an active, intrinsic cell suicide program. We recently suggested that it may have a role in the death of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). We now report that levodopa, the current major therapy for PD, is a potent inducer of apoptosis in cultured postmitotic chick sympathetic neurons. Levodopa, in a concentration range of 0.01-0.3 mM, caused the characteristic apoptotic cascade of cell shrinkage, massive membrane blebbing, and nuclear fragmentation, as evident by nuclear flow cytometry and fluorescence microscopy. Levodopa-induced apoptosis was inhibited by antioxidants, indicating that it may be mediated by autooxidation-reactive species. Levodopa treatment for PD may therefore constitute an additional challenge for the defective apoptosis-inhibiting systems in the nigrostriatal neurons. Despite reassuring data from some, but not all, previous studies, these findings suggest that the possible in vivo toxic effects of levodopa on the survival of the remaining nigral neurons should be further explored.

Animals↗
PubMed1997

Modulation of control mechanisms of dopamine-induced apoptosis--a future approach to the treatment of Parkinson's disease?

The cause for the progressive and selective degeneration of the dopaminergic (DA) nigrostriatal neurons in Parkinson's disease (PD) is still unknown. We suggest a novel approach, that links this neuronal degenerative process to inappropriate triggering of apoptosis, an active, controlled program of cellular self destruction, by excess oxidative stress mediated by DA metabolism. In support of this concept, we found that DA, the endogenous neurotransmitter, is capable of initiating apoptosis in cultured, postmitotic chick sympathetic neurons, an observation further extended to other cellular systems (PC-12 cells, cerebellar granular cells, thymocytes, splenocytes). In comparing the relative apoptosis-triggering potency of other mononamine neurotransmitters, DA was found to be the most active, whereas norepinephrine and serotonin had a moderate and a mild effects, respectively. This grading can be correlated with the relative involvement of the relevant neuronal systems (i.e., substantia nigra, locus ceruleus and raphe nuclei) in PD. We therefore hypothesize that neuronal degeneration in PD may be caused, at least in part, by a failure, either inherited or acquired, in cellular control systems of apoptosis, that may normally restrain the lethal potential of these endogenous neuro-transmitters and their potentially-toxic oxidation products. We therefore point at apoptosis-control systems as a critical scene of events, where the fate of nigrostriatal neurons is ultimately determined, and whose modulation may yield attenuation of the neuronal degenerative process. In support of this concept, we found that vector-driven stable expression of the proto-oncogene bcl-2, an inhibitor of apoptosis, can exert powerful cellular protection against DA toxicity in rat pheochromocytoma PC-12 cells. Furthermore, cell extracts from bcl-2-expressing cells were found to markedly inhibit in vitro oxidation of DA and production of DA-melanin. We also found that expression of bcl-2 can inhibit the decrease in intracellular reduced thiol (-SH) groups which we observed following exposure to DA. Research of the bcl-2 system and associated control mechanisms of apoptosis, possibly acting in association with intra-cellular anti-oxidant pathways, may therefore lead to novel therapeutic approaches for neuroprotection in PD.

Animals↗
PubMed1997

Nigrostriatal neuronal death in Parkinson's disease--a passive or an active genetically-controlled process?

The cause for the rather selective degeneration of the nigrostriatal dopaminergic (DA) neurons in Parkinson's disease (PD) is still enigmatic. The major current hypothesis suggests that nigral neuronal death in PD is due to excessive oxidant stress generated by auto- and enzymatic oxidation of DA, formation of neuromelanin and presence of high concentrations of iron. Such cell death is generally regarded as a passive, necrotic process, mainly resulting from membrane lipid peroxidation, leading to its dysfunction and rupture and then to neuronal disintegration. We suggest a novel approach, that views neuronal degeneration in PD as an active process that occurs mainly the nuclear level. Our concept is based on the following observations: (1) Nigral histopathology in PD is characterized by a slow, protracted degeneration of individual neurons. We propose that it may be due to apoptosis [programmed cell-death (PCD), an active, genetically-controlled, intrinsic program of cell "suicide"] rather than to necrotic cell death. (2) DA exerts antitumor effect on melanoma and neuroblastoma cells. (3) Many anticancer drugs, trigger PCD by causing DNA damage. (4) DA has been shown to be genotoxic. (5) We recently first showed that DA, the endogenous neurotransmitter in the nigra, can trigger apoptosis in cultured, postmitotic sympathetic neurons. (6) We have also shown that PC-12 cells, transfected with the bcl-2 gene (a proto-oncogene that inhibits PCD) are relatively resistant to DA-apoptotic effect. Degeneration of nigrostriatal neurons in PD may therefore be linked to dysregulation of the control mechanisms that normally restrain the PCD-triggering-potential of their own neurotransmitter.

Animals↗
PubMed1997

Dopamine-melanin induces apoptosis in PC12 cells; possible implications for the etiology of Parkinson's disease.

The function of neuromelanin (NM), the oxidized dopamine (DA) polymer, within the DA-producing cells in the human and primate substantia nigra (SN), is still an enigma. Some studies show that the vulnerability of nigral neurons in Parkinson's disease is correlated to their toxic NM content, while others suggest that it contributes to cellular protection. We showed recently that DA, the endogenous nigral neurotransmitter, triggers apoptosis, an active program of cellular self-destruction, in neuronal cultures. In the present study, we exposed cells to synthetic dopamine-melanin (DA-M) and analysed the cellular and genetic changes. We found that exposure of PC12 cells to DA-M (0.5 mg/ml for 24 h) caused 50% cell death, as indicated by trypan blue exclusion assay and 3H-thymidine incorporation. Gel electrophoresis DNA analysis of PC12 cells treated with DA-M showed the typical apoptotic DNA ladder, indicating inter-nucleosomal DNA degradation. The DNA fragmentation also was visualized histochemically in situ by DNA end-labeling staining (the TUNEL method). The FeCl2 (0.05 mM) significantly increased DA-M toxicity, while desferrioxamine, an iron chelator, totally abolished the additive toxicity of iron. The contribution of oxidative stress in this model of DA-M-induced cell death was examined using various antioxidants. In contrast to DA, inhibition of DA-M toxicity antioxidants by reduced glutathione (GSH), N-acetyl cysteine, catalase and Zn/Cu superoxide dismutase (SOD) was very limited. In conclusion, we found that DA-M may induce typical apoptotic death in PC12 cells. Our findings support a possible role of NM in the vulnerability of the dopaminergic neural degeneration in Parkinson's disease. The differential protective effect by antioxidants against toxicity of DA and DA-M may have implications for future neuroprotective therapeutic approaches for this common neurological disorder.

Animals↗
PubMed1997

Monoamine-induced apoptotic neuronal cell death.

1. The monoamines dopamine (DA), norepinephrine (NE), epinephrine (E), and serotonin (5-HT) serve as endogenous neurotransmitters in the nervous system. We recently reported that the neurotransmitter DA can trigger apoptosis (programmed cell death; PCD) in cultured, postmitotic chick embryo sympathetic neurons, suggesting a role for apoptosis in degenerative processes such as Parkinson's disease (PD). However, PD is also associated with involvement of other monoaminergic (MA) neuronal systems (noradrenergic and serotoninergic), though to a lesser extent. 2. We therefore tested the apoptosis-triggering potential of NE, E, and 5-HT in comparison to the DA effect, in cultured postmitotic nerve growth factor (NGF)-dependent chick embryo sympathetic neurons and mouse cerebellar granule cells. 3. In both model systems MA induced neuronal attrition characteristic of apoptosis. MA caused marked morphological alterations: severe neuronal soma shrinkage, membrane blebbing, nuclear condensation and fragmentation, and axonal disintegration. Flow-cytometric analysis of propidium iodide-stained cell nuclei revealed characteristic apoptotic nuclear fragmentation. MA-induced apoptosis could be blocked by SH-group containing antioxidants but not by inhibitors of transcription and translation. 4. Comparison between the two model systems revealed that the cerebellar granule neurons were distinctly more sensitive to the neurotoxic potential of the MA than sympathetic neuronal cells. Significant differences in the dose dependencies and time course of the apoptotic effect were observed among the examined MA, graded as DA > NE approximately E > 5-HT. 5. We conclude that the apoptosis triggering potential, probably mediated by oxidative metabolites, is shared by all MA tested, but with differential time course and dose dependencies. A correlation can be drawn between the effects of DA vs NE vs 5-HT and the relative involvement of dopaminergic/noradrenergic/serotoninergic pathways in PD, which may suggest a common multisystem underlying abnormality in neuronal apoptosis-control mechanisms.

Animals↗
PubMed1997

Dopamine-induced apoptosis is inhibited in PC12 cells expressing Bcl-2.

1. Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). It is assumed that the lethal trigger is the accumulation of oxidative reactive species generated during metabolism of the natural neurotransmitter dopamine. 2. We have recently shown that dopamine is capable of inducing programmed cell death (PCD) or apoptosis in cultured postmitotic chick sympathetic neurons and rat PC12 pheochromocytoma cells. 3. The bcl-2 gene encodes a protein which blocks physiological PCD in many mammalian cells. In an attempt to elucidate further the mechanism of dopamine toxicity, we examined the potential protective effect of bcl-2 in PC12 cells which were transfected with the protooncogene. 4. In our experiments, Bcl-2 producing cells showed a marked resistance to dopamine toxicity. The percentage of nuclear condensation and DNA fragmentation visualized by the end-labeling method following dopamine treatment was significantly lower in bcl-2 expressing cells. Bcl-2 did not protect PC12 cells against toxicity induced by exposure to dopamine-melanin. Extracts of PC12 cells containing Bcl-2 inhibited dopamine autooxidation and formation of dopamine-melanin. Furthermore, the presence of Bcl-2 protected cells from thiol imbalance and prevented thiol loss following exposure to dopamine. 5. The protective effects of Bcl-2 against dopamine toxicity may be explained, in part, by its action as an antioxidant and by its interference in the production of toxic agents. The possible protection by Bcl-2 against neuronal degeneration caused by dopamine may play a role in the pathogenesis of PD and may provide a new direction for the development of neuroprotective therapies.

Animals↗
PubMed1997

The proto-oncogene Bcl-2 inhibits cellular toxicity of dopamine: possible implications for Parkinson's disease.

It is currently believed that excessive oxidant stress induced by metabolism of dopamine (DA), plays a major role in the pathogenesis of the selective nigrostriatal neuronal loss in Parkinson's disease. We recently showed that the neurotransmitter DA, in physiological concentrations, is capable of initiating apoptosis in cultured, post-mitotic sympathetic neurons. Bcl-2 is a proto-oncogene that blocks apoptosis. We now report that Bcl-2 is a powerful inhibitor of DA toxicity in PC-12 pheochromocytoma cells. We induced stable expression of Bcl-2 in PC-12 cells by transfection with recombinant pCMV5 expression vector, containing mouse bcl-2 (coding-sequence) cDNA. Cells expressing Bcl-2 manifested marked resistance to otherwise lethal (300 uM) in vitroconcentrations of DA. This protective effect was reflected in the trypan-blue test of cell survival, 3 H-thymidine incorporation and inhibition of the characteristic apoptotic morphologic alterations in scanning electron microscopic studies. Bcl-2 and associated control systems of apoptosis may have an important physiological role in restraining the apop-tosis-triggering potential of DA in nigrostriatal neurons. This novel field of research may yield insights into the pathogenesis of Parkinson's disease and lead to development of novel therapeutic approaches.

Journal Article↗
PubMed1996

Prevention of dopamine-induced cell death by thiol antioxidants: possible implications for treatment of Parkinson's disease.

We have recently shown that dopamine (DA) can trigger apoptosis, an active program of cellular self-destruction, in various neuronal cultures and proposed that inappropriate activation of apoptosis by DA and or its oxidation products may initiate nigral cell loss in Parkinson's disease (PD). Since DA toxicity may be mediated via generation of oxygen-free radical species, we examined whether DA-induced cell death in PC12 cells may be inhibited by antioxidants. We have found that the thiol containing compounds, reduced glutathione (GSH), N-acetyl-cysteine (NAC), and dithiothreitol (DTT) were markedly protective, while vitamins C and E had lesser or no effect. The thiol antioxidants and vitamin C but not vitamin E, prevented dopamine autooxidation and production of dopamine-melanin. Their protective effect has also manifested by inhibiting DA-induced apoptosis; DNA fragmentation was prevented as was shown histochemically by the in situ end-labeled DNA technique (TUNEL). Intracellular GSH and other thiols constitute an important natural defense against oxidative stress. We have found that depletion of cellular GSH by the addition of phoron, a substrate of glutathione transferase, and buthionine sulfoximine (BSO), an inhibitor of gamma-glutamyl transpeptidase, significantly enhanced DA toxicity. Cotreatment with NAC rescued the cells from the toxic effect of BSO+DA, and phoron+ DA, while addition of GSH provided only partial protection from BSO+DA toxicity. Our data indicate that the thiol family of antioxidants, but not vitamins C and E, are highly effective in rescuing cells from DA-induced apoptosis. Further study of the mechanisms underlying the unique protective capacity of thiol antioxidants may lead to the development of new neuroprotective therapeutic strategies for PD.

Acetylcysteine↗
PubMed1996

Detection of proviral human T-cell lymphotrophic virus type I DNA in mouthwash samples of HAM/TSP patients and HTLV-I carriers.

Human T-cell lymphotrophic virus type I (HTLV-I), is a member of the oncogenic retroviruses family endemic in several parts of the world and also recently identified in the Jewish Mashhadi population who immigrated from Iran to Israel. The virus is the causative agent of adult T-cell leukemia (ATL) and a chronic myelopathy known both as tropical spastic paraparesis (TSP) or HTLV-I associated myelopathy (HAM). The known modes of HTLV-I transmission are by sexual intercourse, from mother to child in breast milk, via blood transfusion, and by sharing of needles by parenteral drug users. In the present study we examined the presence of HTLV-I provirus genomic DNA by nested polymerase chain reaction (PCR) and by DNA hybridization in mouthwash samples obtained from 13 Mashhadi-born Iranian Jews with spastic paraparesis associated with HTLV-I, 4 Mashhadi-born Iranian Jews asymptomatic carriers for HTLV-I and 21 healthy controls. Proviral HTLV-I DNA was detected by mouthwash PCR in 12 of 17 HTLV-I infected subjects (71%) but in none of 21 controls. Proviral DNA was also detected in mouthwash samples using HTLV-I probe by dot blot hybridization assay. The presence of HTLV-I proviral DNA in whole saliva may suggest a possible transmission of the virus via saliva and explain the increased rate of infection in elderly Mashhadi-Jewish population.

Base Sequence↗
PubMed1995

Dopamine-induced programmed cell death in mouse thymocytes.

Exposure of mouse thymocytes to dopamine caused apoptosis (programmed cell death). This was manifested by cellular condensation and membrane damage shown by flow cytometry measurements and scanning electron microscopic study. Dopamine also affected thymocytic nuclei and their genomic DNA integrity. Most of the DNA molecules accumulated in a subdiploid peak in flow cytometry analysis, indicating DNA fragmentation to small particles. DNA analysis showed the typical pattern of 'DNA ladder' caused by internucleosomal DNA cleavage. X-ray microanalysis of the cellular elements of dopamine-treated cells showed elevation of sodium (Na), chloride (Cl) and calcium (Ca) peaks, accompanied by reduction in phosphate (P) concentrations. Comparison of the potassium (K) and P concentrations showed significant differences between the two major death processes: necrosis (induced by exposure to sodium azide (NaN3)) and apoptosis (induced by dopamine). High concentrations of K indicated cell viability while reductions in P and elevations in Ca levels were found to be typical of apoptotic cell death. The antioxidant dithiothreitol (DTT) suppressed dopamine-induced apoptosis in thymocytes, suggesting that its toxicity may be mediated via generation of reactive oxygen radicals. Our study suggests that under certain circumstances, dopamine and/or its metabolites, may induce a process of apoptotic cell death of the dopamine-producing cells in the substantia nigra. Increased accessibility of dopamine to the nigral cell nucleus or inability to scavenge excess free radicals generated from dopamine oxidation triggering programmed cell death, may cause the progressive nigral degeneration in Parkinson's disease.

Animals↗