Decrease In Striatal Dopamine Research Articles

Vitamin D3 improves iminodipropionitrile-induced tic-like behavior in rats through regulation of GDNF/c-Ret signaling activity.

Children with chronic tic disorders (CTD), including Tourette syndrome (TS), have significantly reduced serum 25-hydroxyvitamin D [25(OH)D]. While vitamin D3 supplementation (VDS) may reduce tic symptoms in these children, its mechanism is unclear. The study aim was to investigate the effects and mechanisms of vitamin D deficiency (VDD) and VDS on TS model behavior. Forty 5-week-old male Sprague-Dawley rats were randomly divided into (n = 10 each): control, TS model, TS model with VDD (TS + VDD), or TS model with VDS (TS + VDS; two intramuscular injections of 20,000IU/200g) groups. The VDD model was diet-induced (0IU vitamin D/kg); the TS model was iminodipropionitrile (IDPN)-induced. All groups were tested for behavior, serum and striatal 25(OH)D and dopamine (DA), mRNA expressions of vitamin D receptor (VDR), glial cell line-derived neurotrophic factor (GDNF), protooncogene tyrosine-protein kinase receptor Ret (c-Ret), and DA D1 (DRD1) and D2 (DRD2) receptor genes in the striatum. TS + VDD had higher behavior activity scores throughout, and higher total behavior score at day 21 compared with TS model. In contrast, day 21 TS + VDS stereotyped behavior scores and total scores were lower than TS model. The serum 25(OH)D in TS + VDD was < 20ng/mL, and lower than control. Striatal DA of TS was lower than control. Compared with TS model, striatal DA of TS + VDD was lower, while in TS + VDS it was higher than TS model. Furthermore, mRNA expression of VDR, GDNF, and c-Ret genes decreased in TS model, and GDNF expression decreased more in TS + VDD, while TS + VDS had higher GDNF and c-Ret expressions. VDD aggravates, and VDS ameliorates tic-like behavior in an IDPN-induced model. VDS may upregulate GDNF/c-Retsignaling activity through VDR, reversing the striatal DA decrease and alleviating tic-like behavior.

The Crucial Roles of Pitx3 in Midbrain Dopaminergic Neuron Development and Parkinson's Disease-Associated Neurodegeneration.

The degeneration of midbrain dopaminergic (mDA) neurons, particularly in the substantia nigra pars compacta (SNc), is one of the most prominent pathological hallmarks of Parkinson's disease (PD). To uncover the pathogenic mechanisms of mDA neuronal death during PD may provide therapeutic targets to prevent mDA neuronal loss and slow down the disease's progression. Paired-like homeodomain transcription factor 3 (Pitx3) is selectively expressed in the mDA neurons as early as embryonic day 11.5 and plays a critical role in mDA neuron terminal differentiation and subset specification. Moreover, Pitx3-deficient mice exhibit some canonical PD-related features, including the profound loss of SNc mDA neurons, a dramatic decrease in striatal dopamine (DA) levels, and motor abnormalities. However, the precise role of Pitx3 in progressive PD and how this gene contributes to mDA neuronal specification during early stages remains unclear. In this review, we updated the latest findings on Pitx3 by summarizing the crosstalk between Pitx3 and its associated transcription factors in mDA neuron development. We further explored the potential benefits of Pitx3 as a therapeutic target for PD in the future. To better understand the transcriptional network of Pitx3 in mDA neuron development may provide insights into Pitx3-related clinical drug-targeting research and therapeutic approaches.

The Protein-Rich Fraction from Spirulina platensis Exerts Neuroprotection in Hemiparkinsonian Rats by Decreasing Brain Inflammatory-Related Enzymes and Glial Fibrillary Acidic Protein Expressions.

Spirulina platensis is a cyanobacterium with high protein content and presenting neuroprotective effects. Now, we studied a protein-enriched fraction (SPF), on behavior, neurochemical and immunohistochemical (IHC) assays in hemiparkinsonian rats, distributed into the groups: SO (sham-operated), 6-hydroxydopamine (6-OHDA), and 6-OHDA (treated with SPF, 5 and 10 mg/kg, p.o., 15 days). Afterward, animals were subjected to behavioral tests and euthanized, and brain areas used for neurochemical and IHC assays. SPF partly reversed the changes in the apomorphine-induced rotations, open field and forced swim tests, and also the decrease in striatal dopamine and 3,4-dihydroxyphenylacetic acid contents seen in hemiparkinsonian rats. Furthermore, SPF reduced brain oxidative stress and increased striatal expressions of tyrosine hydroxylase and dopamine transporter and significantly reduced hippocampal inducible nitric oxide synthase, cyclooxygenase-2 and glial fibrillary acidic protein expressions. The data suggest that the protein fraction from S. platensis, through its brain anti-inflammatory and antioxidative actions, exerts neuroprotective effects that could benefit patients affected by neurodegenerative diseases, like Parkinson's disease.

Repeated administration of N-ethyl-pentedrone induces increased aggression and impairs social exploration after withdrawal in mice

N-ethyl-pentedrone (NEPD, 2-(ethylamino)-1-phenyl-1-pentanone) is one of the latest synthetic cathinone derivatives that emerged into the illicit drug market. This drug has psychostimulant properties and has been related with several intoxications and even fatalities. However, information about the consequences of its acute and repeated consumption is lacking. Thus, the aim of our study was to investigate the behavioral effects after both acute and repeated NEPD exposure as well as the neurochemical changes. Male OF1 mice were treated with an acute dose (1, 3 or 10 mg/kg, i.p.) or received repeated injections of these doses (twice/day, 5 days) of NEPD. Shortly after drug-exposure or during drug-withdrawal, anxiety-like behavior, aggressiveness, social interaction, depressive-like symptoms, body weight and temperature were assessed. Also, monoamine synthesis enzymes, levels of neurotransmitters and their precursors and main metabolites, as well as ΔFosB, were determined in striatum and prefrontal cortex from post-mortem tissue. Acute administration of NEPD induced anxiolytic effects and reduced social exploration whereas during withdrawal after repeated administration the anxiolytic effect had vanished, and the reduced social exploration was still present and accompanied with increased aggressive behavior. Moreover, NEPD (10 mg/kg) induced slight hyperthermia and reduced weight gain during the repeated administration, whereas increased locomotor activity and lack of depressive symptoms were found during withdrawal. This was accompanied by increased plasma corticosterone and decrease in striatal dopamine. Finally, the long-lasting and robust increase in ΔFosB levels found in striatum after NEPD chronic exposure suggests a high risk of dependence. The increased aggressivity and locomotor activity, together with this potential of inducing dependence justify a warning about the risks of consumption of NEPD if translated to humans.

Neuroprotective effects of indole-3-carbinol on the rotenone rat model of Parkinson's disease: Impact of the SIRT1-AMPK signaling pathway

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder. Although mounting studies have been conducted, no effective therapy is available to halt its progression. Indole-3-carbinol (I3C) is a naturally occurring compound obtained by β-thioglucosidase-mediated autolysis of glucobrassicin in cruciferous vegetables. Besides its powerful antioxidant activity, I3C has shown neuroprotection against depression and chemically induced neurotoxicity via its anti-inflammatory and antiapoptotic effects. This study aimed to investigate the neuroprotective effects of I3C against rotenone (ROT)-induced PD in male albino rats. The possible protective mechanisms were also explored. PD was induced by subcutaneous administration of ROT (2 mg/kg) for 28 days. The effects of I3C (25, 50, and 100 mg/kg/day) were assessed by catalepsy test (bar test), spontaneous locomotor activity, rotarod test, weight change, tyrosine hydroxylase (TH) expression, α-synuclein (α-Syn) expression, striatal dopamine (DA) content, and histological examination. The highest dose of I3C (100 mg/kg) was the most effective to prevent ROT-mediated motor dysfunctions and amend striatal DA decrease, weight loss, neurodegeneration, TH expression reduction, and α-Syn expression increase in both the midbrain and striatum. Further mechanistic investigations revealed that the neuroprotective effects of I3C are partially attributed to its anti-inflammatory and antiapoptotic effects and the activation of the sirtuin 1/AMP-activated protein kinase pathway. Altogether, these results suggested that I3C could attenuate biochemical, molecular, and functional changes in a rat PD model with following repeated rotenone exposures.

GLOBAL ONGOING TRENDS IN DRUG DESIGNING FOR THE TREATMENT OF TYPE 2 DIABETES AND NEURODEGENERATIVE DISEASES

T2D and neurodegenerative disorders are the diseases which increases with the age of people. T2D is described by hyperglycaemia, insulin opposition or relative absence of insulin take-up though NDs are described by the decrease in intellectual capacity, diffuse of the amyloid plaques &amp; neurofibrillary tangles in AD and degeneration of dopaminergic neurons in the substantia nigra, prompting a decrease of striatal dopamine (DA) levels in Parkinson’s sickness or disease. Knowing the neurodegenerative infections is critical in guaranteeing sound matured life. Although a few instances of familial neurodegenerative messes have been accounted for, yet the instrument for inconsistent neuronal degeneration remains generally in the shade [1]. Since traditional medications neglect to outperform the regular CNS defensive hindrances, along these lines, all together to conquer these obstacles, designated drug conveyance is of first importance for the treatment of Advertisement and Parkinson’s disease. New age of medications has found through creative nanotechnology approaches, for example, polymeric nanoparticles are encouraginggenerators in the sighting of Promotion in light of the fact that nanoparticles are equipped for opening the tight intersections, crossing the BBB[2]. In this way, we can receive the updated things and fresher techniques, for example, nanotechnological, computational and quality treatment approaches for drug plan and conveyance.

Neuroinflammation in Parkinson´s Disease: role of cholesterol

Neuroinflammation in Parkinson´s Disease: role of cholesterol

The Role of Cholesterol in α-Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease.

ABSTRACTParkinson's disease (PD) is a progressive neurodegenerative disease where dopaminergic neurons in the substantia nigra are lost, resulting in a decrease in striatal dopamine and, consequently, motor control. Dopaminergic degeneration is associated with the appearance of Lewy bodies, which contain membrane structures and proteins, including α‐synuclein (α‐Syn), in surviving neurons. PD displays a multifactorial pathology and develops from interactions between multiple elements, such as age, environmental conditions, and genetics. Mutations in the GBA1 gene represent one of the major genetic risk factors for PD. This gene encodes an essential lysosomal enzyme called β‐glucocerebrosidase (GCase), which is responsible for degrading the glycolipid glucocerebroside into glucose and ceramide. GCase can generate glucosylated cholesterol via transglucosylation and can also degrade the sterol glucoside. Although the molecular mechanisms that predispose an individual to neurodegeneration remain unknown, the role of cholesterol in PD pathology deserves consideration. Disturbed cellular cholesterol metabolism, as reflected by accumulation of lysosomal cholesterol in GBA1‐associated PD cellular models, could contribute to changes in lipid rafts, which are necessary for synaptic localization and vesicle cycling and modulation of synaptic integrity. α‐Syn has been implicated in the regulation of neuronal cholesterol, and cholesterol facilitates interactions between α‐Syn oligomers. In this review, we integrate the results of previous studies and describe the cholesterol landscape in cellular homeostasis and neuronal function. We discuss its implication in α‐Syn and Lewy body pathophysiological mechanisms underlying PD, focusing on the role of GCase and cholesterol. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

The N-Methyl-(2S, 4R)-trans-4-hydroxy-L-proline-Enriched Methanol Fraction from Sideroxylon obtusifolium Shows an Anticonvulsant Activity Associated with its Anti-inflammatory/Antioxidant Actions

AbstractEpilepsy is a neurological disorder characterized by recurrent seizures, resulting from excessive neuronal discharges. Sideroxylon obtusifolium is used in Brazil for its anti-inflammatory/antioxidant properties, known to be involved with epilepsy. The anticonvulsant effects of the methanol fraction from S. obtusifolium leaves, rich in N-methyl-(2S,4R)-trans-4-hydroxy-L-proline, were investigated on pilocarpine- and pentylenetetrazole-induced convulsion models. Mice were pretreated with N-methyl-(2S,4R)-trans-4-hydroxy-L-proline (50, 100, 200 mg/kg, p.o.) and, 1 h later, by pilocarpine (400 mg/kg, i.p.) or pentylenetetrazole (80 mg/kg, i.p.). The animals were observed for latency to the first convulsion and latency to death. Immediately after death, brain areas from the pilocarpine groups were harvested for biochemical measurements. The latency to the first convulsion and latency to death increased after N-methyl-(2S,4R)-trans-4-hydroxy-L-proline treatment compared with the pilocarpine- or pentylenetetrazole-only groups. In both convulsion models, sodium valproate (reference drug) was used as a positive control. Additionally, the decreases in striatal dopamine and 3,4-dihydroxyphenylacetic acid contents observed in the pilocarpine-only group were partially prevented in the N-methyl-(2S,4R)-trans-4-hydroxy-L-proline-treated groups. While brain gamma-aminobutyric acid and glutamate contents decreased and increased, respectively, after pilocarpine only, these changes were also prevented by N-methyl-(2S,4R)-trans-4-hydroxy-L-proline. Similarly, N-methyl-(2S,4R)-trans-4-hydroxy-L-proline reduced the brain oxidative stress by decreasing the levels of nitrite and lipid peroxidation and increasing the glutathione content of the pilocarpine-only group. The increases in hippocampal expressions for interleukin 6, interferon-gamma, and glial fibrillary acidic protein, after pilocarpine only, were decreased to normal levels by N-methyl-(2S,4R)-trans-4-hydroxy-L-proline. In conclusion, the study showed significant anticonvulsant effects for N-methyl-(2S,4R)-trans-4-hydroxy-L-proline, probably related to its anti-inflammatory/antioxidant properties. N-Methyl-(2S,4R)-trans-4-hydroxy-L-proline effects were potentiated by VPA (sodium valproate), thus it may also interact with the GABAergic system, as we had recently shown.

Activation of AMPK/aPKCζ/CREB pathway by metformin is associated with upregulation of GDNF and dopamine

Parkinson’s disease (PD) is the second most common neurodegenerative disease, which is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to a decrease in striatal dopamine. There is no antiparkinsonian therapy that offers a true disease-modifying treatment till date and there is an urgent need for a safe and effective neuroprotective or neurorestorative therapy. Our previous study demonstrated that metformin upregulated dopamine in the mouse brain and provided significant neuroprotection in animal model of PD. Therefore, we designed this study to investigate the molecular mechanism underlying such pharmacological effect of metformin. Herein, we found that metformin enhanced the phosphorylation of tyrosine hydroxylase (TH) which was accompanied by increase in brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and activation of their downstream signaling pathways in the mouse brain and SH-SY5Y cells. We further investigated the role of the neurotrophic factors in the activation of TH and observed that both BDNF and GDNF-induction were essential for metformin-induced TH activation. We found that the AMPK/aPKCζ/CREB pathway was essential for metformin-induced GDNF upregulation and TH activation. Thus, this study reveals the TH-activating property of metformin in the brain via induction of neurotrophic factors along with the signaling mechanism. These results potentiate the candidacy of metformin not only as a neuroprotective agent, but also as restorative therapy for the treatment of PD.

Levodopa Therapy for Parkinson's Disease: History, Current Status and Perspectives.

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by a preferential degeneration of dopaminergic neurons in the substantia nigra pars compacta. This results in a profound decrease of striatal dopamine (DA) levels, which in turn leads to the cardinal motor symptoms of PD; muscle rigidity, hypo- and bradykinesia and resting tremor. Even 50 years after its initial use, the DA precursor levodopa (L-dopa), is still the most effective medical therapy for the symptomatic treatment of PD. Long-term L-dopa treatment is however, unfortunately associated with undesirable side effects such as motor fluctuations and dyskinesias. Furthermore, despite the disease alleviating effects of L-dopa, it is still discussed whether L-dopa has a neurotoxic or neuroprotective effect on dopaminergic neurons. Here we review the history of L-dopa, including its discovery, development and current use in the treatment of PD. We furthermore review current evidence of the L-dopa-induced side effects and perspectives of L-dopa treatment in PD compared to other established treatments such as DA-agonists and the inhibitors of catechol-o-methyltransferase and monoamine oxidase B.

The assessment of possible gender-related effect of endogenous striatal alpha-tocopherol level on MPTP neurotoxicity in mice

Several studies supported an increased vulnerability of males regarding Parkinson's disease (PD) and its animal models, the background of which has not been exactly revealed, yet. In addition to hormonal differences, another possible factor behind that may be a female-predominant increase in endogenous striatal alpha-tocopherol (αT) level with aging, even significant at 16 weeks of age, previously demonstrated by the authors. Accordingly, the aim of the current study was the assessment whether this difference in striatal αT concentration may contribute to the above-mentioned distinct vulnerability of genders to nigrostriatal injury.Female and male C57Bl/6 mice at the age of 16 weeks were injected with 12 mg/kg body weight 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 5 times at 2 h intervals or with saline. The levels of some biogenic amines (striatum) and αT (striatum and plasma) were determined by validated high performance liquid chromatography methods.Although the results proved previous findings, i.e., striatal dopamine decrease was less pronounced in females following MPTP treatment, and striatal αT level was significantly higher in female mice, the correlation between these 2 variables was not significant. Surprisingly, MPTP treatment did not affect striatal αT concentrations, but significantly decreased plasma αT levels without differences between genders.The current study, examining the possible role of elevated αT in female C57Bl/6 mice behind their decreased sensitivity to MPTP intoxication for the first time, was unable to demonstrate any remarkable connection between these 2 variables. These findings may further confirm that αT does not play a major role against neurotoxicity induced by MPTP.

Neuroprotective effects of Pulicaria undulata essential oil in rotenone model of parkinson's disease in rats: Insights into its anti-inflammatory and anti-oxidant effects

Parkinson's disease (PD) is a neurodegenerative disorder described by severe motor symptoms involving postural imbalance, uncontrolled shake, slowness of motion and rigidity. Searching for a natural remedy for PD to overcome the common adverse effects of conventional treatments, the neuroprotective effects of three dose levels (50, 100, and 200 mg/kg) of Pulicaria undulata essential oil (PUEO) in rotenone-induced model in male Wistar rats were investigated. PUEO was analyzed by GC and GC/MS resulting in the identification of twenty-one compounds. Carvotanacetone was the major component (80.14%). The middle and high doses of PUEO attenuated rotenone-induced behavioral deficits besides, hindering the decrease in striatal dopamine and ATP levels, with partial retardation in rotenone-induced body weight loss. Biochemical assessments illustrated that PUEO mitigated rotenone-induced increment in striatal interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS). The reduction in malondialdehyde and increase in glutathione striatal contents depicted its antioxidant potential. Molecular docking study of carvotanacetone might justify the observed normalization of the elevated iNOS level induced after exposure to rotenone. This is the first study indicating the ability of PUEO to protect rats against rotenone-induced PD via anti-inflammatory and antioxidant activities with the ability to reduce α-synuclein gene expression.

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) localized protein that regulates ER homeostasis and unfolded protein response (UPR). The biology of endogenous MANF in the mammalian brain is unknown and therefore we studied the brain phenotype of MANF-deficient female and male mice at different ages focusing on the midbrain dopamine system and cortical neurons. We show that a lack of MANF from the brain led to the chronic activation of UPR by upregulation of the endoribonuclease activity of the inositol-requiring enzyme 1α (IRE1α) pathway. Furthermore, in the aged MANF-deficient mouse brain in addition the protein kinase-like ER kinase (PERK) and activating transcription factor 6 (ATF6) branches of the UPR pathways were activated. Neuronal loss in neurodegenerative diseases has been associated with chronic ER stress. In our mouse model, increased UPR activation did not lead to neuronal cell loss in the substantia nigra (SN), decrease of striatal dopamine or behavioral changes of MANF-deficient mice. However, cortical neurons lacking MANF were more vulnerable to chemical induction of additional ER stress in vitro We conclude that embryonic neuronal deletion of MANF does not cause the loss of midbrain dopamine neurons in mice. However, endogenous MANF is needed for maintenance of neuronal ER homeostasis both in vivo and in vitro.

Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson\u2019s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease with limited treatment options. Therefore, the identification of therapeutic targets is urgently needed. Previous studies have shown that the ligand activation of the sigma-1 chaperone (Sigma1R) promotes neuroprotection. The multitarget drug afobazole (5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was shown to interact with Sigma1Rs and prevent decreases in striatal dopamine in the 6-hydroxydopamine (6-OHDA)-induced parkinsonism model. The aim of the present study was to elucidate the role of Sigma1Rs in afobazole pharmacological activity. Using ICR mice we found that administration of afobazole (2.5 mg/kg, i.p.) or selective agonist of Sigma1R PRE-084 (1.0 mg/kg, i.p.) over 14 days normalizes motor disfunction and prevents decreases in dopamine in the 6-OHDA-lesioned striatum. Afobazole administration also prevents the loss of TH + neurons in the substantia nigra. The pre-administration of selective Sigma1R antagonist BD-1047 (3.0 mg/kg, i.p.) abolishes the activity of either afobazole or PRE-084, as determined using the rotarod test and the analysis of striatal dopamine content. The current study demonstrates the contribution of Sigma1Rs in the neuroprotective effect of afobazole in the 6-OHDA model of Parkinson’s disease and defines the therapeutic perspective of Sigma1R agonists in the clinic.

Aspidosperma pyrifolium Mart: neuroprotective, antioxidant and anti-inflammatory effects in a Parkinson's disease model in rats.

Aspidosperma species are used for several diseases, especially for malaria in Brazil. Although the genus is object of pharmacological studies, almost none are found on Aspidosperma pyrifolium. We investigate neuroprotective, antioxidant and anti-inflammatory properties of the APSE-Aq fraction (benzoic acid glycosylated derivative) on Parkinson's disease model. Male Wistar rats were subjected to a 6-hydroxydopamine injection into the right striatum and treated or not with APSE-Aq (100 or 200 mg/kg, p.o.). The sham-operated group was injected with saline. Two weeks later, animals were subjected to behavioural, neurochemical and immunohistochemical evaluation. The data were analysed by ANOVA and Tukey test. The APSE-Aq-treated group shows a partial recovery of behavioural changes as compared with the untreated-6-hydroxydopamine group. A partial recovery was also observed in nitrite contents and lipid peroxidation. APSE-Aq treatments significantly reversed decreases in striatal dopamine and metabolites in the untreated 6-hydroxydopamine group. Immunostainings for markers as tyrosine hydroxylase and dopamine transporter decreased in the untreated 6-hydroxydopamine group and values recovered after APSE-Aq treatments. Similar data were seen for TNF-alpha. APSE-Aq presents neuroprotective, antioxidant and anti-inflammatory activities. Considering that APSE-Aq is chemically related to salicylic acid, it may act on similar targets.

(Invited) Real-Time Striatal Measurements of Oxidative Stress and Dopamine in the Dyskinetic Rat during Chronic L-DOPA Treatment for Parkinson’s Disease

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the preferential loss of dopaminergic neurons stemming from the substantia nigra pars compacta and innervating the dorsal striatum. The substantial decreases in striatal dopamine (DA) result in devastating hypokinetic movements and motor disturbances. Increased generation of reactive oxygen species, such as hydrogen peroxide (H2O2), is also thought to contribute to Parkinsonian symptoms. However, the precise role of H2O2 in the initiation, progression, and maintenance of the disease remains unclear, as reactive oxygen species are difficult to monitor in brain tissue. Further, several lines of evidence suggest that the standard treatment strategy of dopaminergic replacement therapy via administration of Levodopa (L-DOPA; L-3,4 dihydroxyphenylalanine) may serve to increase oxidative stress and potentiate cell death. We are investigating how striatal H2O2 and DA dynamics underlie behavioral changes that result from chronic L-DOPA administration in a rodent model of PD (unilateral 6-OHDA lesion) using fast-scan cyclic voltammetry, an electrochemical technique that affords precise spatial and temporal resolution, as well as selective detection of these neurochemicals. Specifically, carbon-fiber microelectrodes are used to simultaneously quantify rapid H2O2 and DA fluctuations at single recording sites in the dorsal striatum over several weeks of L-DOPA administration. The chemical fluctuations are correlated with behavioral abnormalities that develop over the course of treatment. These studies are advancing our understanding of how oxidative stress modulates nigrostriatal DA signaling, and are demonstrating how these signals correspond with dyskinetic movements in the treatment of PD.

Dissociation of Striatal Dopamine and Tyrosine Hydroxylase Expression from Aging-Related Motor Decline: Evidence from Calorie Restriction Intervention.

The escalating increase in retirees living beyond their eighth decade brings increased prevalence of aging-related impairments, including locomotor impairment (Parkinsonism) that may affect ~50% of those reaching age 80, but has no confirmed neurobiological mechanism. Lifestyle strategies that attenuate motor decline, and its allied mechanisms, must be identified. Aging studies report little to moderate loss of striatal dopamine (DA) or tyrosine hydroxylase (TH) in nigrostriatal terminals, in contrast to ~70%-80% loss associated with bradykinesia onset in Parkinson's disease. These studies evaluated the effect of ~6 months 30% calorie restriction (CR) on nigrostriatal DA regulation and aging-related locomotor decline initiated at 12 months of age in Brown-Norway Fischer F1 hybrid rats. The aging-related decline in locomotor activity was prevented by CR. However, striatal DA or TH expression was decreased in the CR group, but increased in substantia nigra versus the ad libitum group or 12-month-old cohort. In a 4- to 6-month-old cohort, pharmacological TH inhibition reduced striatal DA ~30%, comparable with decreases reported in aged rats and the CR group, without affecting locomotor activity. The dissociation of moderate striatal DA reduction from locomotor activity seen in both studies suggests that aging-related decreases in striatal DA are dissociated from locomotor decline.

Neuroprotective effects of total flavonoid fraction of the Epimedium koreanum Nakai extract on dopaminergic neurons: In vivo and in vitro

Flavonoids, the active components of Epimedii Genus, have been demonstrated to protect against osteoporosis, cardiovascular diseases and rheumatoid arthritis. The present study aimed to investigate the neuroprotective effects of total flavonoid (TF) fraction of Epimedium koreanum Nakai on dopaminergic neurons in the cellular and mice models of Parkinson's disease (PD). TF pretreatment could ameliorate the decrease of striatal dopamine (DA) content and the loss of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra pars compacta (SNpc) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). TF treatment could reverse the changes of Bcl-2 and Bax protein expressions in the striatum of PD mice. 1-Methyl-4-phenylpyridinium ion (MPP+) significantly decreased the cell viability and mitochondrial membrane potential in MES23.5 cells. These effects could be reversed by TF treatment. In addition, MPP+-induced changes of Bcl-2 and Bax mRNA and protein expressions were also reversed by TF pretreatment. These data demonstrated that TF of E. koreanum Nakai could protect against MPTP-induced dopaminergic neuronal death in mice and MPP+-induced neurotoxicity in dopaminergic MES23.5 cells. Anti-apoptosis might be involved in this process.

Nigral injection of a proteasomal inhibitor, lactacystin, induces widespread glial cell activation and shows various phenotypes of Parkinson's disease in young and adult mouse.

Proteinaceous inclusions, called Lewy bodies, are used as a pathological hallmark for Parkinson's disease (PD). Lewy bodies contain insoluble α-synuclein (aSyn) and many other ubiquitinated proteins, suggesting a role for protein degradation system failure in the PD pathogenesis. Indeed, proteasomal dysfunction has been linked to PD but commonly used in vivo toxin models, such as 6-OHDA or MPTP, do not have a significant effect on the proteasomal system or protein aggregation. Therefore, we wanted to study the characteristics of a proteasomal inhibitor, lactacystin, as a PD model on young and adult mice. To study this, we performed stereotactic microinjection of lactacystin above the substantia nigra pars compacta in young (2month old) and adult (12-14month old) C57Bl/6 mice. Motor behavior was measured by locomotor activity and cylinder tests, and the markers of neuroinflammation, aSyn, and dopaminergic system were assessed by immunohistochemistry and HPLC. We found that lactacystin induced a Parkinson's disease-like motor phenotype 5-7days after injection in young and adult mice, and this was associated with widespread neuroinflammation based on glial cell markers, aSyn accumulation in substantia nigra, striatal dopamine decrease, and loss of dopaminergic cell bodies in the substantia nigra and terminals in the striatum. When comparing young and adult mice, adult mice were more sensitive for dopaminergic degeneration after lactacystin injection that further supports the use of adult mice instead of young when modeling neurodegeneration. Our data showed that lactacystin is useful in modeling various aspects of Parkinson's disease, and taken together, our findings emphasize the role of a protein degradation deficit in Parkinson's disease pathology, and support the use of proteasomal inhibitors as Parkinson's disease models.