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Synapse 04/2012; 66(8):755-7. · 2.94 Impact Factor
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ABSTRACT: Calcitriol, the active metabolite of vitamin D, has been shown to have significant effects on the brain. These actions include reducing the severity of some central nervous system lesions, possibly by upregulating trophic factors such as glial cell line-derived neurotrophic factor (GDNF). GDNF has substantial effects on the nigrostriatal dopamine (DA) system of young adult, aged and lesioned animals. Thus, the administration of calcitriol may lead to significant effects on nigrostriatal DA neuron functioning. The present experiments were designed to examine the ability of calcitriol to alter striatal DA release, and striatal and nigral tissue levels of DA. Male Fischer-344 rats were administered vehicle or calcitriol (0.3, 1.0, or 3.0 μg/kg, s.c.) once daily for eight consecutive days. Three weeks later in vivo microdialysis experiments were conducted to measure basal and stimulus evoked overflow of DA from the striatum. Basal levels of extracellular DA were not significantly affected by the calcitriol treatments. However, the 1.0 and 3.0 μg/kg doses of calcitriol led to increases in both potassium and amphetamine evoked overflow of striatal DA. Although post-mortem tissue levels of striatal DA were not altered by the calcitriol injections, nigral tissue levels of DA and its main metabolites were increased by both the 1.0 and 3.0 μg/kg doses of calcitriol. In a separate group of animals GDNF levels were augmented in the striatum and substantia nigra after eight consecutive daily injections of calcitriol. These results suggest that systemically administered calcitriol can upregulate dopaminergic release processes in the striatum and DA levels in the substantia nigra. Increases in the levels of endogenous GDNF following calcitriol treatment may in part be responsible for these changes. The ability of calcitriol to lead to augmented DA release in the striatum suggests that calcitriol may be beneficial in disease processes involving dopaminergic dysfunction.
Neurochemistry International 11/2011; 60(2):186-91. · 2.86 Impact Factor
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ABSTRACT: PTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca²+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1⁻/⁻ mice.
Purified brain mitochondria of Pink1⁻/⁻ mice showed impaired Ca²+ storage capacity, resulting in increased Ca²+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1⁻/⁻ mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1⁻/⁻ mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1⁻/⁻ mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1⁻/⁻ embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1⁻/⁻ mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting.
Increased mitochondrial Ca²+ sensitivity and JNK activity are early defects in Pink1⁻/⁻ mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1⁻/⁻ mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant expression of genes that regulate innate immune responses. While some differentially expressed genes may mitigate neurodegeneration, increased LPS-induced brain cytokine expression and impaired cytokine-induced NF-κB activation may predispose neurons of Pink1⁻/⁻ mice to inflammation and injury-induced cell death.
PLoS ONE 01/2011; 6(1):e16038. · 4.09 Impact Factor
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ABSTRACT: Neurturin (NTN), a member of the glial cell line-derived neurotrophic factor (GDNF) family, has substantial effects on normal and lesioned nigrostriatal dopamine systems. However, its ability to protect against toxin-induced loss of striatal dopamine release has not been previously reported. The goal of the present study was to determine if NTN could protect against 6-hydroxydopamine (6-OHDA)-induced reductions in striatal dopamine overflow and tissue levels of dopamine and to compare the effects of NTN with those of GDNF. Male Fischer-344 rats were given a single injection of vehicle, or 5 microg NTN or GDNF, into the right striatum. The following day the animals were given a single injection of 12 microg 6-OHDA into the striatum at the same site where the trophic factor was injected. Microdialysis experiments conducted three weeks later indicated that the 6-OHDA decreased basal levels of dopamine and metabolites in the lesioned striatum compared to the contralateral striatum, and NTN was able to partially protect against the 6-OHDA-induced reductions. Injection of NTN one day prior to 6-OHDA also led to significant protection against loss of both potassium- and amphetamine-evoked overflow of dopamine. The NTN treatments partially protected against 6-OHDA-induced reductions in striatal tissue levels of dopamine and completely protected against loss of nigral dopamine content. The protective effects of NTN were similar in magnitude to those of GDNF. These results support that within the experimental parameters used in this study, NTN is as effective as GDNF in protecting against the dopamine-depleting effects of intrastriatal 6-OHDA.
Neurochemistry International 11/2010; 57(5):540-6. · 2.86 Impact Factor
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ABSTRACT: Neurturin (NTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family; and, while GDNF has been shown to increase dopamine (DA) release in normal animals, the ability of NTN to alter DA release has not been previously reported. The purpose of the present study was to determine if NTN could alter striatal DA release, and to compare the effects of NTN to GDNF. Male Fischer-344 rats were given a single injection of vehicle or 5 microg NTN or GDNF into the right substantia nigra. Three weeks later microdialysis experiments were conducted to assess striatal DA release. Basal extracellular levels of striatal DA were not affected by either NTN or GDNF. However, both NTN and GDNF led to increases in amphetamine-evoked overflow of DA from the ipsilateral striatum, and there was a trend for potassium-evoked overflow to be augmented. Postmortem tissue levels of DA were decreased by approximately 20% in the striatum, and increased by approximately 100% in the substantia nigra, on the ipsilateral side of the brain compared to the contralateral side following both NTN and GDNF injection. Thus, NTN, like GDNF, can augment striatal DA release, and the magnitude of the NTN effects are similar to those of GDNF.
Neurochemical Research 05/2010; 35(5):727-34. · 2.24 Impact Factor
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ABSTRACT: Trichloroethylene, a chlorinated solvent widely used as a degreasing agent, is a common environmental contaminant. Emerging evidence suggests that chronic exposure to trichloroethylene may contribute to the development of Parkinson's disease. The purpose of this study was to determine if selective loss of nigrostriatal dopaminergic neurons could be reproduced by systemic exposure of adult Fisher 344 rats to trichloroethylene. In our experiments, oral administration of trichloroethylene induced a significant loss of dopaminergic neurons in the substantia nigra pars compacta in a dose-dependent manner, whereas the number of both cholinergic and GABAergic neurons were not decreased in the striatum. There was a robust decline in striatal levels of 3, 4-dihydroxyphenylacetic acid without a significant depletion of striatal dopamine. Rats treated with trichloroethylene showed defects in rotarod behavior test. We also found a significantly reduced mitochondrial complex I activity with elevated oxidative stress markers and activated microglia in the nigral area. In addition, we observed intracellular alpha-synuclein accumulation in the dorsal motor nucleus of the vagus nerve, with some in nigral neurons, but little in neurons of cerebral cortex. Overall, our animal model exhibits some important features of Parkinsonism, and further supports that trichloroethylene may be an environmental risk factors for Parkinson's disease.
Journal of Neurochemistry 11/2009; 112(3):773-83. · 4.06 Impact Factor
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ABSTRACT: A role for inflammation has been hypothesized in the etiology and progression of Parkinson's disease (PD). In this study, we generated, characterized, and validated the first progressive PD-related mouse model (C57/B6) with intrastriatal injection of lipopolysaccharide (LPS). We showed progressive and specific dopaminergic neurodegeneration in the substantia nigra, which is accompanied by striatal dopamine depletion and progressive behavioral impairment, which was alleviated by the use of the PD drug L-Dopa. We focused on the role of nitric oxide (NO) in inflammation-promoted cell death and suggest that the expression of the inducible NO synthase plays a role in the progressive loss of dopaminergic neurons but not the initial loss induced by LPS. With this model, future research can be performed in gene knockout mice to study other potential mechanisms of inflammation-induced neurodegeneration. In addition, this model can be used to screen therapeutics for PD at a more clinically relevant time (i.e., after LPS injection but before manifestation of PD-related behavioral impairment), because most PD drugs are screened in animal models in which inhibitors are given predisease induction. Thus, this novel PD-related model should be further characterized and strongly considered as a tool for future drug studies.
Journal of Neuroscience Research 03/2009; 87(8):1913-21. · 2.74 Impact Factor
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ABSTRACT: Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disorder with unknown cause, but it has been suggested that neuroinflammation may play a role in pathogenesis of the disease. Neuroinflammatory component in process of PD neurodegeneration was proposed by postmortem, epidemiological and animal model studies. However, it remains unclear how neuroinflammatory factors contribute to dopaminergic neuronal death in PD.
In this study, we analyzed the relationship among inducible nitric oxide synthase (iNOS)-derived NO, mitochondrial dysfunction and dopaminergic neurodegeneration to examine the possibility that microglial neuroinflammation may induce dopaminergic neuronal loss in the substantia nigra. Unilateral injection of lipopolysaccharide (LPS) into the striatum of rat was followed by immunocytochemical, histological, neurochemical and biochemical analyses. In addition, behavioral assessments including cylinder test and amphetamine-induced rotational behavior test were employed to validate ipsilateral damage to the dopamine nigrostriatal pathway. LPS injection caused progressive degeneration of the dopamine nigrostriatal system, which was accompanied by motor impairments including asymmetric usage of forelimbs and amphetamine-induced turning behavior in animals. Interestingly, some of the remaining nigral dopaminergic neurons had intracytoplasmic accumulation of alpha-synuclein and ubiquitin. Furthermore, defect in the mitochondrial respiratory chain, and extensive S-nitrosylation/nitration of mitochondrial complex I were detected prior to the dopaminergic neuronal loss. The mitochondrial injury was prevented by treatment with L-N(6)-(l-iminoethyl)-lysine, an iNOS inhibitor, suggesting that iNOS-derived NO is associated with the mitochondrial impairment.
These results implicate neuroinflammation-induced S-nitrosylation/nitration of mitochondrial complex I in mitochondrial malfunction and subsequent degeneration of the nigral dopamine neurons.
PLoS ONE 02/2009; 4(5):e5482. · 4.09 Impact Factor
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ABSTRACT: Evidence suggests chronic inflammation and iron accumulation may play a role in the pathogenesis of Parkinson's disease (PD) as inflammation and iron levels increase with age and appear in the disease pathology. It is hypothesized that an aggravated inflammatory response and iron accumulation, as a function of age, increase oxidative stress and participate in the pathogenesis of PD. Intracranial injection of the bacterial endotoxin, lipopolysaccharide (LPS), has been shown to induce microglia activation, oxidative stress, mitochondrial impairment, iron accumulation, and dopaminergic neurodegeneration within the substantia nigra. We tested the hypothesis that injection of LPS into the striatum would increase iron accumulation in the substantia nigra of aged rats compared to young ones. Our results showed that four weeks post injection, LPS significantly increased microglia activation, lipid peroxidation, ferritin expression, and total nigral iron content in aged rats. In addition, LPS significantly altered the turnover ratio of homovanillic acid to dopamine. Thus, an age-related increase in iron as well as susceptibility to inflammation may play an important role in PD-related neurodegeneration, as free radicals produced from the inflammatory response can become more toxic through increased ferrous iron catalyzed Fenton chemistry. This may enhance oxidative stress, exacerbate microglia activation, and drive the progression of PD.
Current Aging Science 07/2008; 1(2):112-21.
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Don M Gash,
Kathryn Rutland,
Naomi L Hudson,
Patrick G Sullivan,
Guoying Bing, Wayne A Cass,
Jignesh D Pandya,
Mei Liu,
Dong-Yong Choi,
Randy L Hunter,
Greg A Gerhardt,
Charlie D Smith,
John T Slevin,
T Scott Prince
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ABSTRACT: To analyze a cluster of 30 industrial coworkers with Parkinson's disease and parkinsonism subjected to long-term (8-33 years) chronic exposure to trichloroethylene.
Neurological evaluations were conducted on the 30 coworkers, including a general physical and neurological examination and the Unified Parkinson's Disease Rating Scale. In addition, fine motor speed was quantified and an occupational history survey was administered. Next, animal studies were conducted to determine whether trichloroethylene exposure is neurotoxic to the nigrostriatal dopamine system that degenerates in Parkinson's disease. The experiments specifically analyzed complex 1 mitochondrial neurotoxicity because this is a mechanism of action of other known environmental dopaminergic neurotoxins.
The three workers with workstations adjacent to the trichloroethylene source and subjected to chronic inhalation and dermal exposure from handling trichloroethylene-soaked metal parts had Parkinson's disease. Coworkers more distant from the trichloroethylene source, receiving chronic respiratory exposure, displayed many features of parkinsonism, including significant motor slowing. Neurotoxic actions of trichloroethylene were demonstrated in accompanying animal studies showing that oral administration of trichloroethylene for 6 weeks instigated selective complex 1 mitochondrial impairment in the midbrain with concomitant striatonigral fiber degeneration and loss of dopamine neurons.
Trichloroethylene, used extensively in industry and the military and a common environmental contaminant, joins other mitochondrial neurotoxins, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and some pesticides, as a risk factor for parkinsonism.
Annals of Neurology 03/2008; 63(2):184-92. · 11.09 Impact Factor
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ABSTRACT: In evaluating discrepant results between experiments in our laboratory, we collected data that challenge the notion that anthelminthic drugs like FBZ do not alter inflammatory responses. We found that FBZ significantly modulates inflammation in F344 rats intrastriatally injected with LPS. FBZ treatment of LPS-injected rats significantly increased weight loss, microglial activation, and dopamine loss; in addition, FBZ attenuated the LPS-induced loss of astrocytes. Therefore, FBZ treatment altered the effects of LPS injection. Caution should be used in interpreting data collected from rats treated with LPS and FBZ.
Comparative medicine 11/2007; 57(5):487-92. · 1.05 Impact Factor
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ABSTRACT: HIV-1 infection with concurrent methamphetamine (MA) abuse results in exacerbated neurodegenerative changes and rapid progression of a form of sub-cortical dementia termed HIV-1 associated dementia (HAD). A notable feature of HAD is the involvement of the dopaminergic system manifested as parkinsonian like movement abnormalities. The HIV-1 transactivator of transcription (Tat) protein is very often used in experimental studies trying to understand neurotoxic consequences of HIV-1 infection, since the pathophysiological changes induced by Tat mirrors, in part, the means by which HIV-1 infection of the nervous system results in neuronal damage. Understanding the interaction of Tat and MA in the basal ganglia and the resultant injury to the dopaminergic system in rodent models as well as cell culture will shed light on the dopaminergic pathology occurring in HIV-1 infected-MA abusers. The aim of this review is to update the reader on the current knowledge of MA and HIV-1 neurotoxicity, specifically Tat, and discuss the progress in understanding how MA synergizes with the HIV-1 transactivator protein Tat to damage the basal ganglia.
Current HIV research 06/2007; 5(3):301-13. · 1.98 Impact Factor
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ABSTRACT: Evidence suggests that chronic inflammation, mitochondrial dysfunction, and oxidative stress play significant and perhaps synergistic roles in Parkinson's disease (PD), where the primary pathology is significant loss of the dopaminergic neurons in the substantia nigra. The use of anti-inflammatory drugs for PD treatment has been proposed, and inhibition of cyclo-oxygenase-2 (COX-2) or activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) yields neuroprotection in MPTP-induced PD. Lipopolysaccharide (LPS) induces inflammation-driven dopaminergic neurodegeneration. We tested the hypothesis that celecoxib (Celebrex, COX-2 inhibitor) or pioglitazone (Actos, PPAR-gamma agonist) will reduce the LPS-induced inflammatory response, spare mitochondrial bioenergetics, and improve nigral dopaminergic neuronal survival. Rats were treated with vehicle, celecoxib, or pioglitazone and were intrastriatally injected with LPS. Inflammation, mitochondrial dysfunction, oxidative stress, decreased dopamine, and nigral dopaminergic neuronal loss were observed post-LPS. Celecoxib and pioglitazone provided neuroprotective properties by decreasing inflammation and restoring mitochondrial function. Pioglitazone also attenuated oxidative stress and partially restored striatal dopamine as well as demonstrated dopaminergic neuroprotection and reduced nigral microglial activation. In summary, intrastriatal LPS served as a model for inflammation-induced dopaminergic neurodegeneration, anti-inflammatory drugs provided protective properties, and pioglitazone or celecoxib may have therapeutic potential for the treatment of neuro-inflammation and PD.
Journal of Neurochemistry 04/2007; 100(5):1375-86. · 4.06 Impact Factor
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ABSTRACT: Nornicotine, a tobacco alkaloid and N-demethylated nicotine metabolite, releases DA from superfused rat striatal slices in a mecamylamine-sensitive manner, indicating nicotinic receptor (nAChR) modulation of this response. The current study determined the effect of nornicotine on rat striatal dopamine transporter (DAT) function using in vivo voltammetry. In a dose-related and mecamylamine-sensitive manner, nornicotine (0.35-12.0 mg/kg, s.c.) decreased DA clearance, suggesting that nornicotine inhibits striatal DAT function via a nAChR-mediated mechanism. Furthermore, the nAChRs mediating the nornicotine-induced inhibition of DAT function appear to be different from those activated by nicotine which increases DA clearance. Understanding the actions of nornicotine in brain may have significance for emerging therapeutics and for the management of nicotine dependence.
Synapse 04/2007; 61(3):157-65. · 2.94 Impact Factor
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ABSTRACT: Many current theories of Parkinson's disease (PD) suggest that oxidative stress is involved in the neurodegenerative process. Potential neuroprotective agents could protect neurons through inherent antioxidant properties or through the upregulation of the brain's antioxidant defenses. Glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore dopamine neurons in experimental models of PD and to improve motor function in human patients. This study was designed to investigate GDNF's effect on oxidative stress in a model of PD. GDNF or vehicle was injected into the right striatum of male Fischer-344 rats. Three days later 6-OHDA or saline was injected into the same striatum. The striatum and substantia nigra from both sides of the brain were removed 24h after 6-OHDA or saline injection and analyzed for the oxidative stress markers protein carbonyls and 4-hydroxynonenal. Both markers were significantly reduced in GDNF+6-OHDA treated animals compared to vehicle+6-OHDA treated animals. In addition, in animals allowed to recover for 3.5-4 weeks after the 6-OHDA administration, the GDNF led to significant protection against loss of striatal and nigral tissue levels of dopamine. These results suggest that the protective effects of GDNF against 6-OHDA involve a reduction in oxidative stress.
Neuroscience Letters 03/2007; 412(3):259-63. · 2.11 Impact Factor
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ABSTRACT: Changes in the nigrostriatal system may be involved with the motor abnormalities seen in aging. These perturbations include alterations in dopamine (DA) release, regulation and transport in the striatum and substantia nigra, striatal atrophy and elevated iron levels in the basal ganglia. However, the relative contribution of these changes to the motor deficits seen in aging is unclear. Thus, using the rhesus monkey as a model, the present study was designed to examine several of these key alterations in the basal ganglia in order to help elucidate the mechanisms contributing to age-related motor decline. First, 32 female rhesus monkeys ranging from 4 to 32 years old were evaluated for their motor capabilities using an automated hand-retrieval task. Second, non-invasive MRI methods were used to estimate brain composition and to indirectly measure relative iron content in the striatum and substantia nigra. Third, in vivo microdialysis was used to evaluate basal and stimulus-evoked levels of DA and its metabolites in the striatum and substantia nigra of the same monkeys. Our results demonstrated significant decreases in motor performance, decreases in striatal DA release, and increases in striatal iron levels in rhesus monkeys as they age from young adulthood. A comprehensive statistical analysis relating age, motor performance, DA release, and iron content indicated that the best predictor of decreases in motor ability, above and beyond levels of performance that could be explained by age alone, was iron accumulation in the striatum. This suggests that striatal iron levels may be a biomarker of motor dysfunction in aging; and as such, can be monitored non-invasively by longitudinal brain MRI scans. The results also suggest that treatments aimed at reducing accumulation of excess iron in the striatum during normal aging may have beneficial effects on age-related deterioration of motor performance.
Neurobiology of aging 03/2007; 28(2):258-71. · 5.94 Impact Factor
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ABSTRACT: The current study examined whether environmental enrichment alters the effects of monoamine-depleting doses of methamphetamine on subsequent methamphetamine-induced hyperactivity and conditioned place preference. Rats were raised in either an enriched or isolated condition from 21 to 55 days of age and then were treated with monoamine-depleting doses of methamphetamine (10 mg/kg, four injections at 2 h intervals) or saline. Eight days later, rats were assessed for methamphetamine-induced (0.3 or 1.0 mg/kg) hyperactivity and conditioned place preference. Results indicated that the monoamine-depleting dose regimen produced a similar hyperthermic response in enriched and isolated rats. Enriched and isolated rats also displayed a similar depletion of dopamine in the striatum and serotonin in nucleus accumbens. The monoamine-depleting dose regimen, however, enhanced methamphetamine hyperactivity across repeated conditioning sessions in enriched rats, but not in isolated rats. In contrast to isolated rats, enriched rats failed to display significant conditioned place preference to the low dose of methamphetamine (0.3 mg/kg) following the monoamine-depleting dose regimen, suggesting that the rewarding effect of methamphetamine was blunted by the combined effect of enrichment and methamphetamine treatment. Thus, environmental enrichment may exacerbate the behavioral consequences of monoamine-depleting doses of methamphetamine.
Behavioural Pharmacology 10/2006; 17(5-6):499-508. · 2.72 Impact Factor
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ABSTRACT: Our previous studies demonstrated that the psychostimulant methamphetamine (MA) and the human immunodeficiency virus-1 (HIV-1) protein Tat interacted to cause enhanced dopaminergic neurotoxicity. The present study examined whether tumor necrosis factor-alpha (TNF-alpha) mediates the interaction between Tat and MA. In Sprague-Dawley rats, injections of Tat caused a small but significant increase in striatal TNF-alpha level, whereas MA resulted in no change. The increase in TNF-alpha induced by Tat + MA was not significantly different from that induced by Tat alone. Temporal analysis of TNF-alpha levels revealed a 50-fold increase 4 h after Tat administration. In C57BL/6 mice, Tat + MA induced a 50% decline in striatal dopamine levels, which was significantly attenuated in mice lacking both receptors for TNF-alpha. TNF-alpha synthesis inhibitors significantly attenuated Tat + MA neurotoxicity in hippocampal neuronal culture. The results suggest that Tat-induced elevation of TNF-alpha may predispose the dopaminergic terminals to subsequent damage by MA.
Neurobiology of Disease 10/2006; 23(3):663-8. · 5.40 Impact Factor
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ABSTRACT: Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in striatal dopamine (DA) content. It has previously been shown that glial cell line-derived neurotrophic factor (GDNF) can reduce the DA-depleting effects of neurotoxic doses of METH. However, there are several other trophic factors that are protective against dopaminergic toxins. Thus, the present experiments further investigated the protective effect of GDNF as well as the protective effects of several other trophic factors. Male Fischer-344 rats were given an intracerebral injection of trophic factor (2-10 microg) 1 day before METH (5 mg/kg, s.c., 4 injections at 2-h intervals). Seven days later DA levels in the striatum were measured using high-performance liquid chromatography (HPLC). Initial experiments indicated that only intrastriatal GDNF, and not intranigral GDNF, was protective. Thereafter, all other trophic factors were administered into the striatum. Members of the GDNF family (GDNF, neurturin, and artemin) all provided significant protection against the DA-depleting effects of METH, with GDNF providing the greatest protection. Brain-derived neurotrophic factor, neurotrophin-3, acidic fibroblast growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, transforming growth factor-alpha (TGF-alpha), heregulin beta1 (HRG-beta1), and amphiregulin (AR) provided no significant protection at the doses examined. These results suggest that the GDNF family of trophic factors can provide significant protection against the DA-depleting effects of neurotoxic doses of METH.
Annals of the New York Academy of Sciences 09/2006; 1074:272-81. · 3.15 Impact Factor
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ABSTRACT: Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in brain dopamine (DA) and serotonin (5-HT) content. Calcitriol, the active metabolite of vitamin D, has potent effects on brain cells, both in vitro and in vivo, including the ability to upregulate trophic factors and protect against various lesions. The present experiments were designed to examine the ability of calcitriol to protect against METH-induced reductions in striatal and nucleus accumbens levels of DA and 5-HT. Male Fischer-344 rats were administered vehicle or calcitriol (1 microg/kg, s.c.) once a day for eight consecutive days. After the seventh day of treatment the animals were given METH (5 mg/kg, s.c.) or saline four times in 1 day at 2-h intervals. Seven days later the striata and accumbens were harvested from the animals for high-performance liquid chromatography (HPLC) analysis of monoamines and metabolites. In animals treated with vehicle and METH, there were significant reductions in DA, 5-HT, and their metabolites in both the striatum and accumbens. In animals treated with calcitriol and METH, the magnitude of the METH-induced reductions in DA, 5-HT, and metabolites was substantially and significantly attenuated. The calcitriol treatments did not reduce the hyperthermia associated with multiple injections of METH, indicating that the neuroprotective effects of calcitriol are not due to the prevention of increases in body temperature. These results suggest that calcitriol can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of METH.
Annals of the New York Academy of Sciences 09/2006; 1074:261-71. · 3.15 Impact Factor
