DA Loss Research Articles

α-Synuclein induces Th17 differentiation and impairs the function and stability of Tregs by promoting RORC transcription in Parkinson's disease

BackgroundParkinson’s disease (PD) is characterized by the loss of dopaminergic neurons (DA) and the accumulation of Lewy body deposits composed of alpha-Synuclein (α-Syn), which act as antigenic epitopes to drive cytotoxic T-cell responses in PD. Increased T helper 17 (Th17) cells and dysfunctional regulatory T cells (Tregs) have been reported to be associated with the loss of DA in PD. However, the mechanism underlying the Th17/Treg imbalance remains unknown. MethodsHere, we examined the percentage of Th17 cells, the percentage of Tregs and the α-Syn level and analysed their correlations in the peripheral blood of PD patients and in the substantia nigra pars compacta (SNpc) and spleen of MPTP-treated mice and A53 transgenic mice. We assessed the effect of α-Syn on the stability and function of Tregs and the differentiation of Th17 cells and evaluated the role of retinoid-related orphan nuclear receptor (RORγt) upregulation in α-Syn stimulation in vivo and in vitro. ResultsWe found that the α-Syn level and severity of motor symptoms were positively correlated with the increase in Th17 cells and decrease in Tregs in PD patients. Moreover, α-Syn stimulation led to the loss of Forkhead box protein P3 (FOXP3) expression in Tregs, accompanied by the acquisition of IL-17A expression. Increased Th17 differentiation was detected upon α-Syn stimulation when naïve CD4+ T cells were cultured under Th17-polarizing conditions. Mechanistically, α-Syn promotes the transcription of RORC, encoding RORγt, in Tregs and Th17 cells, leading to increased Th17 differentiation and loss of Treg function. Intriguingly, the increase in Th17 cells, decrease in Tregs and apoptosis of DA were suppressed by a RORγt inhibitor (GSK805) in MPTP-treated mice. ConclusionTogether, our data suggest that α-Syn promotes the transcription of RORC in circulating CD4+ T cells, including Tregs and Th17 cells, to impair the stability of Tregs and promote the differentiation of Th17 cells in PD. Inhibition of RORγt attenuated the apoptosis of DA and alleviated the increase in Th17 cells and decrease in Tregs in PD.

6-Hydroxydopamine lesion and levodopa treatment modify the effect of buspirone in the substantia nigra pars reticulata.

Background and Purpose l‐DOPA‐induced dyskinesia (LID) is considered a major complication in the treatment of Parkinson's disease (PD). Buspirone (5‐HT1A partial agonist) have shown promising results in the treatment of PD and LID, however no 5‐HT‐based treatment has been approved in PD. The present study was aimed to investigate how the substantia nigra pars reticulata (SNr) is affected by buspirone and whether it is a good target to study 5‐HT antidyskinetic treatments.Experimental ApproachBuspirone was studied using in vivo single‐unit, electrocorticogram, local field potential recordings along with microdialysis and immunohistochemistry in naïve/sham, 6‐hydroxydopamine (6‐OHDA)‐lesioned or 6‐OHDA‐lesioned and l‐DOPA‐treated (6‐OHDA/l‐DOPA) rats.Key ResultsLocal buspirone inhibited SNr neuron activity in all groups. However, systemic buspirone reduced burst activity in 6‐OHDA‐lesioned rats (with or without l‐DOPA treatment), whereas 8‐OH‐DPAT, a full 5‐HT1A agonist induced larger inhibitory effects in sham animals. Neither buspirone nor 8‐OH‐DPAT markedly modified the low‐frequency oscillatory activity in the SNr or synchronization within the SNr with the cortex. In addition, local perfusion of buspirone increased GABA and glutamate release in the SNr of naïve and 6‐OHDA‐lesioned rats but no effect in 6‐OHDA/l‐DOPA rats. In the 6‐OHDA/l‐DOPA group, increased 5‐HT transporter and decreased 5‐HT1A receptor expression was found.Conclusions and ImplicationsThe effects of buspirone in SNr are influenced by dopamine loss and l‐DOPA treatment. The present results suggest that the regulation of burst activity of the SNr induced by DA loss may be a good target to test new drugs for the treatment of PD and LID.

A small dose of apomorphine counteracts the deleterious effects of middle cerebral artery occlusion in different models.

The present manuscript investigates in two animal species by using two different experimental models of middle cerebral artery occlusion (permanent and transient), the neuroprotective effects of the dopamine receptor agonist apomorphine. These effects were evaluated by measuring the infarct volume and by counting muscle strength at different time points following the ischemic insult. Apomorphine at the dose of 3 mg/Kg when adminsitered at two hours following the occlusion of the middle cerebral artery was able to reduce significantly the infarct volume in the cortex of mice and the ischemic volume of the basal ganglia perfused by the perforant branches of the middle cerebral artery in the rat. In this latter case the behavioral evaluation (i.e. muscle strength) was preserved most effectively in the contralateral side at 24 and 72 hours. The present findings contribute to foster the concept that DA agonists might be useful in the treatment of cerebral ischemia. At the same time the behavioral improvement induced by DA administration following basal ganglia ischemia may be interpreted as the effects of an authentic disease modifying effect rather than a simple symtomatic relief due to a potential loss of DA containing axons in the basal ganglia. These data add on previous evidence showing analogous effects induced by the DA precursor L-DOPA. Apart from providing an evidence of a neuroprotective effect induced by increased DA stimulation the present data call for further studies aimed at comparing the effects of apomorphine with other DA agonists. In fact the quinoline moiety of apomorphine was claimed to protect neurons from a variety of insults independently from a DA agonist activity. The induction of protein clearing pathways appears to be potentially relevant for these effects.

Material Properties of Crushable Concrete for Use in Vehicle Antiram Barriers

AbstractWith raised national security awareness because of terroristic threats, more focus recently has been placed on barrier and safety systems that can prevent the loss of life and structural da...

A potential compensatory role for endogenous striatal tyrosine hydroxylase-positive neurons in a nonhuman primate model of Parkinson's disease.

The possibility of enhancing endogenous brain repair following neurological disorders, such as Parkinson's disease (PD), is of considerable recent interest. One such mechanism may exist in the striatum as an upregulated population of tyrosine hydroxylase (TH)-immunoreactive neurons that appear after 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) lesions in nonhuman primates as well as in humans with PD. An intriguing possibility is that these endogenous neurons reflect a compensatory mechanism to mitigate the loss of striatal DA due to progressive destruction of the nigrostriatal pathway. The possibility of enhancing the number and function of this population is attractive; however, it is crucial to gain further information about these cells in order to comprehend more fully their possible therapeutic potential. The current research was designed to investigate the fate of this endogenous population in African green monkeys rendered parkinsonian by MPTP lesions. Specifically, we assessed changes in the numbers of striatal neurons expressing TH at differing stages of the toxin-induced behavioral disability and discovered a close relationship with symptom severity and striatal DA neuron numbers. Increased numbers of striatal TH-positive neurons were associated with MPTP treatment that produced parkinsonian symptoms compared to numbers of these neurons in MPTP-treated asymptomatic animals and untreated controls. Expression of striatal DA neurons peaked at the manifestation of symptoms in mild/moderate animals and remained stable in animals that were severely parkinsonian. Furthermore, in severely debilitated animals that improved after fetal dopaminergic grafts, we discovered a return to control levels of the endogenous population. Taken together, our results further support the concept that this population of DA neurons responds to variations in striatal DA tone and may serve as a compensatory mechanism to restore striatal DA levels in the context of significant depletion. Artificially manipulating this endogenous population could prove beneficial for PD treatment, especially for individuals in early disease stages.

Dietary supplementation with resveratrol protects against striatal dopaminergic deficits produced by in utero LPS exposure

The purpose of this study was to determine the effect of dietary supplementation with the anti-inflammatory compound resveratrol in pregnant dams on lipopolysaccharide (LPS)-induced dopaminergic deficits in pups exposed to LPS in utero. Gravid female rats were fed with a resveratrol-enriched diet during gestational days 3–22.5 (E3–E22.5) and received an intraperitoneal (i.p.) injection of 1mg/kg LPS at E10.5. The striata were isolated from the pups at postnatal days 10 (P10) and P21. LPS-induced dopaminergic deficits were noted at P21, but not P10. These DA deficits at P21 were exhibited by a loss of DA and DA metabolite [3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] levels and tyrosine hydroxylase (TH) expression in the striatum. The LPS-induced loss of DA, DA metabolites, and TH expression were attenuated in the striata of pups from the dams fed with the resveratrol-supplemented diet. These data suggest that a resveratrol-supplemented diet may restore homeostasis of the striatal DA neuronal system following disruption by LPS.

Orchestrated increase of dopamine and PARK mRNAs but not miR-133b in dopamine neurons in Parkinson's disease

Progressive loss of substantia nigra dopamine neurons (SN DA) is a hallmark of aging and of Parkinson's disease (PD). Mutations in PARK genes cause familial PD forms. Increased expression of alpha-synuclein (PARK4) is a disease-triggering event in familial PD and also observed in SN DA neurons in sporadic PD but related transcriptional changes are unknown. With optimized single-cell quantitative real-time polymerase chain reaction analysis, we compared messenger RNA and microRNA levels in SN DA neurons from sporadic PD patients and controls. Non-optimally matched donor ages and RNA integrities are common problems when analyzing human samples. We dissected the influence of distinct ages and RNA integrities of our samples by applying a specifically-optimized, linear-mixed-effects model to quantitative real-time polymerase chain reaction-data. We identified that elevated alpha-synuclein messenger RNA levels in SN DA neurons of human PD brains were positively correlated with corresponding elevated levels of mRNAs for functional compensation of progressive SN DA loss and for enhanced proteasomal (PARK5/UCHL1) and lysosomal (PARK9/ATPase13A2) function, possibly counteracting alpha-synuclein toxicity. In contrast, microRNA miR-133b levels, previously implicated in transcriptional dysregulation in PD, were not altered in SN DA neurons in PD.

Asymmetric dopamine loss differentially affects effort to maximize gain or minimize loss

BackgroundDopamine (DA) plays an important role in regulating effort expenditure for reward, but whether it is also involved in modulating effort to avoid punishment is not clear. Preference for approach towards rewarding stimuli or away from aversive stimuli is associated with asymmetric activation in anterior brain regions. Asymmetric DA signaling in subcortical-frontal circuits may therefore contribute to differentially energizing behavior towards approach or avoidance behavior. We tested this hypothesis in patients with Parkinson's disease (PD), characterized by asymmetric DA loss. MethodsPatients with greater DA deficit in the left (n = 20) or right (n = 19) hemisphere, performed a task that measures separately effort to approach (maximize gains) versus effort to avoid (minimize loss), on and off DA replacement therapy. ResultsWhen tested off medication, patients with relatively greater DA deficit in the left hemisphere showed greater approach deficit (less effort to increase gain than to avoid loss) whereas the opposite pattern of effort expenditure was demonstrated by patients with greater DA deficit in the right hemisphere. Performing the same task when medicated revealed increased willingness to expend effort, such that increased effort to maximize gain was associated left hemisphere improved DA function (reflected by reduced symptoms), while increased effort to avoid loss was related to right hemisphere improvement. ConclusionsThese results suggest that asymmetry of DA levels modulates the differential exertion of effort toward attaining rewards versus avoiding aversive consequences, providing new insights into understanding the underlying pathophysiology of behavioral syndromes such as apathy and impulsive-compulsive disorders.

The effect of manganese on dopamine toxicity and dopamine transporter (DAT) in control and DAT transfected HEK cells

Chronic exposure to Mn results in the development of a neurological disorder known as manganism characterized by neurological deficits resembling that seen in Parkinsonism. Although dopaminergic neurons within the nigrostriatal pathway appear intact, Mn-induced irregularities in DA transmission have been observed including decreased amphetamine-induced DA release and loss of the dopamine transporter (DAT). Results of studies to evaluate the effect of Mn and DA on cell viability in control and DAT-transfected HEK cells reveal that Mn is equally toxic to both cell lines whereas DA was only toxic to cells containing DAT. DA toxicity was saturable suggesting that transport may be rate limiting. When Mn and DA were added simultaneously to the media, cell toxicity was similar to that produced by Mn alone suggesting that Mn may suppress DA uptake in the DAT containing cells. Preincubation of DA prior to the addition of Mn resulted in cell death which was essentially additive with that produced independently by the two agents. Mn was also shown to decrease DA uptake and amphetamine-induced DA efflux in DAT containing cells. Time-lapsed confocal microscopy indicates that Mn can promote trafficking of cell surface DAT into intracellular compartments which may account for the decrease in DA uptake and DA efflux in these cells. Mn-induced internalization of DAT may provide an explanation for disruption in DA transmission previously reported in the striatum.

Neurochemical changes in animal models of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative syndrome associated with selective loss of dopaminergic neurons in the striatum. It is believed that both mitochondrial dysfunction and oxidative stress (OS) play important role in the pathogenesis of PD. Development of an effective causal therapy should be focused on preventing or at least retarding the neurodegenerative process underlying the disease. In chronic in fusion PD model studied the effect of rotenone on the content, and release of striatal neurotransmitters of rat upon OS by H2O 2 perfusion. The effects of anti-Parkinsonian drugs were examined in vitro rotenone PD, OS slices model. The role of P2X7 receptor (P2X7r) formed by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) or in vitro rotenone treatment using C57/BI6 and P2X7r knockout mice. Neurochemical response was determined using microvolume perfusion method, HPLC separation of dansylated samples. Dopamine o-quinone (DAQ) oxidized metabolite of DA was detected electrochemically at -100 mV potential in reduction working mode. The dopamine content in the rat striatum is decreased in response to chronic intravenous rotenone infusion. However, surviving dopaminergic neurons take up and release only a slightly lower amount of DA in response to electrical stimulation. Striatal dopaminergic neurons showed increased susceptibility to OS, responding with enhanced release of DA and with formation of toxic metabolite DAQ. The loss of DA and ATP and formation of DAQ induced by OS confirmed the impairment of striatum upon in vitro rotenone. Formation of DAQ at the end effect of OS confirmed the impairment of dopaminergic function by rotenone. However, when applied rotenone with l-DOPA treatment the endogenous DAQ was detected in perfusion samples. However, when applied rotenone with l-DOPA treatment the endogenous DAQ was detected in the micro-volume perfusion samples. Conversely, when rasagiline and trolox were in use these DA-quinones metabolites were not detectable. Rotenone treatment elicited a similar reduction in ATP content in the substantia nigra of both genotypes, whereas reduction of ATP was more pronounced after rotenone treatment in striatal slices of P2X7 deficient mice. Although the level of the endocannabinoid, 2-AG, was elevated by rotenone in the striatum of wild-type mice, an effect that was absent in mice deficient in P2X7 receptors. Genetic deletion of P2X7 receptors did not change depletion of striatal endogenous DA content after in vivo MPTP or in vitro rotenone treatment. Although the endogenous amino acids content and the level of the endocannabinoid, AEA was elevated by MPTP in the striatum of mice, but 2-AG remained unchanged in mice deficient in P2X7 receptors. In conclusion, oxidative stress induced, pathological DA release and the formation of toxic metabolites of DA are distinctly modified by the tested antiparkinsonian drugs and P2X7 receptor deficiency does not promote the survival of dopaminergic neurons.

Evaluating the Efficacy of Remifentanil-Propofol versus Isoflurane in Reducing Blood Loss with Considering Depth of Anesthesia during Endoscopic Sinus Surgery

Several methods have been suggested to decrease bleeding during surgery, one of which is the usage of hypotensive anesthetic agents. Endoscopic Sinus Surgery (ESS) is one of the surgeries which need a clear field and the amount of bleeding profoundly impacts the ability of surgeons. Current study was designed to evaluate the effect of remifentanil combined with propofol versus Isoflurane on blood loss during ESS and its possible interaction with Depth of Anesthesia. Fifty one patients comprising 15 females and 36 males undergoing ESS were chosen for this study. One group received propofol and remifentanil to induce and maintain anesthesia and the second group received Isoflurane. Mean Arterial Blood Pressure (MAP), Depth of Anesthesia and total blood loss were recorded for the patients of both group. Data were analyzed using t-test, Repeated Measures ANOVA and Pearson’s correlation. P 0.05 was considered statistically significant. Both agents induced hypotension during surgery. No significant difference was observed in total blood loss between two groups. DA was decreased in both groups, but no significant correlation was found between DA and MAP or DA and blood loss. There is no significant difference between remifentanil combined with propofol and Isoflurane in decreasing blood loss during ESS, thus we suggest usage of hypotensive anesthetic agent regardless of its type is ESS.

Recovery of hypothalamic tuberoinfundibular dopamine neurons from acute toxicant exposure is dependent upon protein synthesis and associated with an increase in parkin and ubiquitin carboxy-terminal hydrolase-L1 expression

Hypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed in acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse and rotenone rat models of degeneration. It is not known if the resistance of TIDA neurons is a constitutive or induced cell-autonomous phenotype for this unique subset of DA neurons. In the present study, treatment with a single injection of MPTP (20mg/kg; s.c.) was employed to examine the response of TIDA versus NSDA neurons to acute injury. An acute single dose of MPTP caused an initial loss of DA from axon terminals of both TIDA and NSDA neurons, with recovery occurring solely in TIDA neurons by 16h post-treatment. Initial loss of DA from axon terminals was dependent on a functional dopamine transporter (DAT) in NSDA neurons but DAT-independent in TIDA neurons. The active metabolite of MPTP, 1-methyl, 4-phenylpyradinium (MPP+), reached higher concentration and was eliminated slower in TIDA compared to NSDA neurons, which indicates that impaired toxicant bioactivation or distribution is an unlikely explanation for the observed resistance of TIDA neurons to MPTP exposure. Inhibition of protein synthesis prevented TIDA neuron recovery, suggesting that the ability to recover from injury was dependent on an induced, rather than a constitutive cellular mechanism. Further, there were no changes in total tyrosine hydroxylase (TH) expression following MPTP, indicating that up-regulation of the rate-limiting enzyme in DA synthesis does not account for TIDA neuronal recovery. Differential candidate gene expression analysis revealed a time-dependent increase in parkin and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) expression (mRNA and protein) in TIDA neurons during recovery from injury. Parkin expression was also found to increase with incremental doses of MPTP. The increase in parkin expression occurred specifically within TIDA neurons, suggesting that these neurons have an intrinsic ability to up-regulate parkin in response to MPTP-induced injury. These data suggest that TIDA neurons have a compensatory mechanism to deal with toxicant exposure and increased oxidative stress, and this unique TIDA neuron phenotype provides a platform for dissecting the mechanisms involved in the natural resistance of central DA neurons following toxic insult.

Nurr1 Is Required for Maintenance of Maturing and Adult Midbrain Dopamine Neurons

Transcription factors involved in the specification and differentiation of neurons often continue to be expressed in the adult brain, but remarkably little is known about their late functions. Nurr1, one such transcription factor, is essential for early differentiation of midbrain dopamine (mDA) neurons but continues to be expressed into adulthood. In Parkinson's disease, Nurr1 expression is diminished and mutations in the Nurr1 gene have been identified in rare cases of disease; however, the significance of these observations remains unclear. Here, a mouse strain for conditional targeting of the Nurr1 gene was generated, and Nurr1 was ablated either at late stages of mDA neuron development by crossing with mice carrying Cre under control of the dopamine transporter locus or in the adult brain by transduction of adeno-associated virus Cre-encoding vectors. Nurr1 deficiency in maturing mDA neurons resulted in rapid loss of striatal DA, loss of mDA neuron markers, and neuron degeneration. In contrast, a more slowly progressing loss of striatal DA and mDA neuron markers was observed after ablation in the adult brain. As in Parkinson's disease, neurons of the substantia nigra compacta were more vulnerable than cells in the ventral tegmental area when Nurr1 was ablated at late embryogenesis. The results show that developmental pathways play key roles for the maintenance of terminally differentiated neurons and suggest that disrupted function of Nurr1 and other developmental transcription factors may contribute to neurodegenerative disease.

Impaired learning and memory in Pitx3 deficient aphakia mice: A genetic model for striatum-dependent cognitive symptoms in Parkinson's disease

Disorders of the basal ganglia such as Parkinson's disease (PD) and Huntington's disease are commonly thought of primarily as motor disorders; however, the cognitive symptoms of these diseases such as executive dysfunction, learning, memory and attention deficits are prominent and often more disabling than the hallmark motor symptoms. Cognitive features of PD are often neglected in preclinical studies of PD, likely due to the lack of available animal models to study them. Aphakia mice, which are deficient in the transcription factor Pitx3, model the selective nigrostriatal DA loss in PD. Here we report that aphakia mice are impaired in striatum-dependent cognitive tasks including rotarod learning, T-maze and inhibitory avoidance tasks, but not the striatum-independent social transmission of food preference task. These results suggest that some neuropsychiatric symptoms in PD are related to the pathophysiology of the disease rather than stress associated with disease burden, or medications used to treat PD. Furthermore aphakia mice may be used as a novel model of non-motor symptoms in PD.

Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease

BackgroundIt has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD.MethodsTwo rodent 'models' of PD, 6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the effects of EX-4. Rats were then investigated in vivo and ex vivo with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system.ResultsEX-4 (0.1 and 0.5 μg/kg) was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats.ConclusionThe apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models of PD, EX-4 is in current clinical use in the management of type-II diabetes and freely crosses the blood brain barrier; hence, assessment of the clinical efficacy of EX-4 in patients with PD could be pursued without delay.

Neglect of memory after dopaminergic lesions in monkeys

Crossed unilateral dopaminergic lesions of the nigrostriatal bundle and unilateral inferotemporal cortex ablations (DA × IT lesions) in marmoset monkeys produced impaired retention of object discriminations first learnt before, or after, the DA lesion but no impairment on new learning of the same type of task. Retention testing of a pre-operatively learned task was given after new learning of a different task so impairment cannot be attributed to improvement with practice or spontaneous recovery. We argue that the DA lesion produces a form of intentional neglect, a defect of volition, which is the mnemonic counterpart of the volitional neglect of directional hypokinesia, which animals with this lesion also exhibit. The DA lesion was unilateral (for welfare reasons) so the information to be retrieved had to be confined to that hemisphere by the use of an IT ablation in the other hemisphere. Unilateral DA lesion compromises the competence of ipsilateral fronto-striatal interactions and our results parallel those found in monkeys with crossed IT × frontal lesions that are impaired on complex tasks requiring effortful implementation of a cognitive strategy but are not impaired on discrimination learning. Parkinsonian patients with sub-total but bilateral DA loss may lack ‘top-down’ conative mechanisms as well as ‘top-down’ movement initiation mechanisms. They may fail to initiate retrieval strategies, although they may not exhibit retrograde amnesia under test conditions that provoke retrieval. Failure to self-initiate retrieval of relevant knowledge may contribute to the paucity of cognitive style and loss of executive skills exhibited by some patients with Parkinson's disease.

Interleukine-1β and interleukine-6 levels in striatum and other brain structures after MPTP treatment: influence of behavioral lateralization

MPTP ( N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces diminution of the dopamine in nigrostriatal pathway and cognitive deficits in mice. MPTP treatment also increases pro-inflammatory cytokine production in substantia nigra and striatum. Since, pro-inflammatory cytokines influence striatal dopamine content and provoke cognitive impairments, the cognitive defects induced by MPTP may be partly due to brain cytokine induction in other structures than nigrostriatal pathway. Furthermore, behavioral lateralization, as assessed by paw preference, influences cytokine production at the periphery and in the central nervous system. Behavioral lateralization may thus influence brain cytokine levels after MPTP. In order to address these issues, mice selected for paw preference were injected with 25 mg/kg MPTP i.p. for five consecutive days after which striatal dopamine and DOPAC contents were measured by HPLC and IL-1β and IL-6 quantified by ELISA in the striatum, cerebral cortex, hippocampus and hypothalamus. The results showed that MPTP treatment induced dramatic loss of DA in striatum, simultaneously, IL-6 levels decreased in the striatum and increased in hippocampus and hypothalamus, while IL-1β levels decreased in the striatum, cerebral cortex and hippocampus. Interestingly, striatal dopamine turnover under basal conditions as well as striatal IL-1β and IL-6 levels under basal conditions and after MPTP depended on behavioral lateralization. Left pawed mice showed a higher decrease in dopamine turnover and lower cytokine levels as compared to right pawed animals. Behavioral lateralization also influenced IL-6 hippocampal levels under basal conditions and IL-1β cortical levels after MPTP. From these results, it can be concluded that MPTP-induced cognitive defects are accompanied by an alteration of pro-inflammatory cytokine levels in brain structures other than those involved in the nigrostriatal pathway. In addition, MPTP-induced dopamine decrease is influenced by behavioral lateralization, possibly through an effect on brain cytokine levels.

Loss of response to levodopa in Parkinson’s disease and co-occurrence with dementia: role of D 3 and not D 2 receptors

Previous data suggest a relationship between the loss of response to levodopa in Parkinson’s disease (PD) patients with the co-occurrence of dementia, but the role of alterations in the dopamine system has not been explored. We measured the extent of striatal DA loss and changes in striatal DA D 2 and D 3 receptors in postmortem striatum of PD patients who historically had or had not lost their clinical response to dopaminergic drugs and/or had an additional diagnosis of dementia. Clinical evaluation and retrospective chart reviews for PD and dementia, and neuropathological diagnoses were obtained. All PD cases (±dementia), regardless of response to dopaminergic drugs, exhibited a significant and similar degree and pattern of loss of tyrosine hydroxylase immunocytochemistry and DA transporter binding in striatum, and loss of tyrosine hydroxylase-immunoreactive neurons and brain-derived neurotrophic-immunoreactive neurons from the ventral midbrain. D 2 receptor concentrations were modestly elevated in the rostral striatum of all the PD cases (±dementia), whether or not they continued to respond to dopaminergic drugs. In contrast, loss of D 3 receptor concentration correlated with loss of response to dopaminergic drugs, independent of the presence or absence of dementia. A maintained response to dopaminergic drugs correlated with an elevation of D 3 receptors. Dementia with PD was highly correlated with a loss of response to dopaminergic drugs, and was also correlated with reduced D 3 receptors. The alterations in D 3 receptor concentrations were greatest in the nucleus accumbens, caudal striatum, and globus pallidus. Thus, loss of dopamine D 3 receptors may be a more important contributing factor to a loss of response to dopaminergic drugs than changes in the D 2 receptor.

Systemic administration of d-amphetamine induced a delayed production of nitric oxide in the striatum of rats

Nitric oxide (NO) is a free-radical gas with a role in various signal transduction processes. In the CNS, NO acts as an important central nervous messenger, but in excess it may be neurotoxic. Chronic or high dose administration of d-amphetamine (AMPH) has been shown to induce striatal neurotoxicity in rodents and primates. In this study, we studied whether AMPH given systemically elicits NO formation in the striatum of rats and determined the relationship between NO formation and striatal DAergic terminal damage. Our results demonstrated that a single large dose administration of AMPH with desipramine elicited a delayed production of NO and concomitant long-term DA loss in the striatum. These phenomena were blocked by treatment with either the nitric oxide synthase inhibitor N G-nitro- l-arginine methyl ester ( l-NAME) or the glutamate N-methyl- d-aspartate antagonist MK-801. It appears that AMPH-induced NO formation is critical for development of long-lasting DAergic terminal toxicity in the striatum of rats.

Role of glutamate in neurodegeneration of dopamine neurons in several animal models of parkinsonism.

Although controversial, studies with methamphetamine and MPTP suggest a link between glutamate-mediated excitotoxicity and degeneration of dopamine cells. Both compounds are thought to create a metabolic stress. To further explore glutamate actions in DA degeneration, we investigated the effects of other metabolic inhibitors. In mesencephalic cultures, DA cell loss produced by 3-NPA or malonate was potentiated by NMDA and prevented by MK-801. In vivo, striatal DA loss produced by intranigral infusions of malonate was also potentiated by intranigral NMDA and prevented by systemic MK-801. In contrast, systemic MK-801 did not prevent DA loss produced by intrastriatal malonate. Intrastriatal MK-801 or CGS 19755 did attenuate DA loss in METH-treated mice, but was confounded by the findings that METH-induced hyperthermia, an important component in toxicity, was also attenuated. Taken together, the data support the hypothesis of NMDA receptor involvement in degeneration of DA neurons. Furthermore, the data also suggest that this interaction is likely to occur in the substantia nigra rather than in the striatum.