Novel D3 dopamine receptor‐preferring agonist D‐264: Evidence of neuroprotective property in Parkinson's disease animal models induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine and lactacystin

Parkinson's disease (PD), a progressive neurodegenerative movement disorder, is known to be caused by diverse pathological conditions resulting from dysfunction of the ubiquitin‐proteasome system (UPS), mitochondria, and oxidative stress leading to preferential nigral dopamine (DA) neuron degeneration in the substantia nigra. In the present study, we evaluated the novel D3 receptor‐preferring agonist D‐264 in a mouse model of PD to evaluate its neuroprotective properties against both the nigrostriatal dopaminergic toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐ and the proteasome inhibitor lactacystin‐induced dopaminergic degeneration. C57BL/6 male mice either were given MPTP by intraperitoneal injection twice per day for 2 successive days at a dose 20 mg/kg or were microinjected with lactacystin bilaterally (1.25 μg/side) into the medial forebrain bundle (MFB). Pretreatment with D‐264 (1 mg/kg and 5 mg/kg, intraperitoneally, once per day), started 7 days before administration of MPTP or lactacystin. We found that D‐264 significantly improved behavioral performance, attenuated both MPTP‐ and lactacystin‐induced DA neuron loss, and blocked proteasomal inhibition and microglial activation in the substantia nigra (SN). Furthermore, D‐264 treatment was shown to increase the levels of brain‐derived neurotrophic factor (BDNF) and glial cell line‐derived factor (GDNF) in MPTP‐ and lactacystin‐treated mice, possibly indicating, at least in part, the mechanism of neuroprotection by D‐264. Furthermore, pretreatment with the D3 receptor antagonist U99194 significantly altered the effect of neuroprotection conferred by D‐264. Collectively, our study demonstrates that D‐264 can prevent neurodegeneration induced by the selective neurotoxin MPTP and the UPS inhibitor lactacystin. The results indicate that D‐264 could potentially serve as a symptomatic and neuroprotective treatment agent for PD. © 2010 Wiley‐Liss, Inc.     

Targeting oxidative stress, mitochondrial dysfunction and neuroinflammatory signaling by selective cyclooxygenase (COX)-2 inhibitors mitigates MPTP-induced neurotoxicity in mice

Several studies have pointed towards the role of oxidative stress, mitochondrial dysfunction and neuroinflammation in Parkinson's disease (PD). The present study was focused on the possible neuroprotective effect of selective cyclooxygenase (COX)-2-inhibitors: valdecoxib and NS-398 in 1-methyl-4-phenyl-1,2,3,6-tertahydropyridine (MPTP)-induced neurotoxicity in mice. MPTP administration in dose of 40 mg/kg, i.p (four injections of 10 mg/kg, i.p. at an interval of 1 h each) significantly induced the Parkinson-like symptoms in mice as indicated by change in locomotor activity, inability to correct posture (bar test), and oxidative stress (increased levels of lipid peroxidation, nitrite concentration, and depletion of antioxidant enzyme). MPTP administration significantly impaired mitochondrial complex-I activity and redox activity, upregulated the caspase-3 and NF-κB levels as compared to vehicle group. Treatment with valdecoxib (5 or 10 mg/kg, p.o.) or NS-398 (5 or 10 mg/kg, p.o.) for 7 days significantly reversed behavioral, biochemical, mitochondrial complex alterations as well as attenuated the induction of proinflammatory mediators in MPTP-treated groups. The findings of the present study substantiate the neuroprotective role of selective COX-2 inhibitors in ameliorating MPTP-induced neurodegeneration in mice and suggest the possible therapeutic potential of these drugs in the management of PD.     

Neuroprotective effects of agmatine in mice infused with a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered impairments in olfactory, cognitive, emotional and motor functions associated with time-dependent disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). Agmatine, an endogenous arginine metabolite, has been proposed as a novel neuromodulator that plays protective roles in several models of neuronal cellular damage. In the present study we demonstrated that repeated treatment with agmatine (30mg/kg, i.p.) during 5 consecutive days increased the survival rate (from 40% to 80%) of 15-month-old C57BL/6 female mice infused with a single intranasal (i.n.) administration of MPTP (1mg/nostril), improving the general neurological status of the surviving animals. Moreover, pretreatment with agmatine was found to attenuate short-term social memory and locomotor activity impairments observed at different periods after i.n. MPTP administration. These behavioral benefits of exogenous agmatine administration were accompanied by a protection against the MPTP-induced decrease of hippocampal glutamate uptake and loss of dopaminergic neurons in the substantia nigra pars compacta of aging mice, without altering brain monoamine oxidase B (MAO-B) activity. These results provide new insights in experimental models of PD, indicating that agmatine represents a potential therapeutic tool for the management of cognitive and motor symptoms of PD, together with its neuroprotective effects.     

Randomized trial of safinamide add‐on to levodopa in Parkinson's disease with motor fluctuations

Levodopa is effective for the motor symptoms of Parkinson's disease (PD), but is associated with motor fluctuations and dyskinesia. Many patients require add‐on therapy to improve motor fluctuations without exacerbating dyskinesia. The objective of this Phase III, multicenter, double‐blind, placebo‐controlled, parallel‐group study was to evaluate the efficacy and safety of safinamide, an α‐aminoamide with dopaminergic and nondopaminergic mechanisms, as add‐on to l ‐dopa in the treatment of patients with PD and motor fluctuations. Patients were randomized to oral safinamide 100 mg/day (n = 224), 50 mg/day (n = 223), or placebo (n = 222) for 24 weeks. The primary endpoint was total on time with no or nontroublesome dyskinesia (assessed using the Hauser patient diaries). Secondary endpoints included off time, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) scores, and Clinical Global Impression‐Change (CGI‐C). At week 24, mean ± SD increases in total on time with no or nontroublesome dyskinesia were 1.36 ± 2.625 hours for safinamide 100 mg/day, 1.37 ± 2.745 hours for safinamide 50 mg/day, and 0.97 ± 2.375 hours for placebo. Least squares means differences in both safinamide groups were significantly higher versus placebo. Improvements in off time, UPDRS Part III, and CGI‐C were significantly greater in both safinamide groups versus placebo. There were no significant between‐group differences for incidences of treatment‐emergent adverse events (TEAEs) or TEAEs leading to discontinuation. The addition of safinamide 50 mg/day or 100 mg/day to l ‐dopa in patients with PD and motor fluctuations significantly increased total on time with no or nontroublesome dyskinesia, decreased off time, and improved parkinsonism, indicating that safinamide improves motor symptoms and parkinsonism without worsening dyskinesia. © 2013 International Parkinson and Movement Disorder Society     

Baicalein attenuates astroglial activation in the 1‐methyl‐4‐phenyl‐1,2,3,4‐tetrahydropyridine‐induced Parkinson's disease model by downregulating the activations of nuclear factor‐κB,ERK, and JNK

In Parkinson's disease (PD), neuroinflammation plays a critical role in the neurodegenerative process. Furthermore, activated microglia and astrocytes, responsible for activated immune response in the central nervous system, are found in regions associated with dopaminergic neuronal death. The flavonoid baicalein is known to have antibacterial, antiviral, and antiinflammatory activities. In the present study, the neuroprotective effects of baicalein were examined in a murine 1‐methyl‐4‐phenyl‐1,2,3,4‐tetrahydropyridine (MPTP) model of PD. Low doses of baicalein improved motor ability and prevented dopaminergic neuron loss caused by MPTP. In addition, microglial and astrocyte activations were reduced in PD mice pretreated with baicalein. Further study of primary astrocytes revealed that baicalein suppressed the 1‐methyl‐4‐phenylpyridine‐induced nuclear translocation of nuclear factor‐κB and reduced the activations of JNK and ERK, suggesting that the neuroprotective effects of baicalein in our PD model were due to attenuated astrocyte activation. The findings of this study indicate that baicalein could be useful for the treatment of PD and other neuroinflammation‐related neurodegenerative diseases. © 2013 Wiley Periodicals, Inc.     

Effect of Oestrogen Receptors on Brain NMDA Receptors of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine Mice

Parkinson’s disease (PD) is characterised by the loss of nigrostriatal dopamine (DA) neurones and glutamate overactivity. There is substantial evidence to suggest that oestrogens prevent or delay the disease. 17β‐oestradiol has neuroprotective effects in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of PD and modulates brain NMDA receptors. In MPTP‐lesioned mice, oestrogen receptor (ER)α and ERβ are important in 17β‐oestradiol‐induced neuroprotection. To evaluate the role of ERs in the response of NMDA receptors to lesion, we compared wild‐type (WT) with ER knockout (KO) C57Bl/6 male mice that received 7, 9 or 11 mg/kg of MPTP. These mice were also treated with MPTP (9 mg/kg) and 17β‐oestradiol. [³H]Ro 25‐6981 specific binding autoradiography was used to label NMDA receptors containing NR2B subunits. In the frontal and cingulate cortex and striatum, vehicle‐treated WT mice had higher [³H]Ro 25‐6981 specific binding compared to ERKO mice. Cortical [³H]Ro 25‐6981 specific binding decreased with increasing doses of MPTP in WT and ERKOα but not ERKOβ mice, whereas a dose‐related decrease was only observed in the striatum of WT mice remaining low in ERKOα and ERKOβ mice. No effect of 17β‐oestradiol treatment in intact or MPTP‐lesioned mice of all three genotypes was observed in the cortex, whereas it increased striatal specific binding of intact ERKOβ and MPTP‐lesioned WT mice. Striatal [³H]Ro 25‐6981 specific binding positively correlated with striatal DA concentrations only in WT mice. MPTP and 17β‐oestradiol treatments had more limited effects in the hippocampus. Only in the CA3 and dentate gyrus did vehicle and 17β‐oestradiol‐treated ERKOα mice have higher [³H]Ro 25‐6981 specific binding than WT and ERKOβ mice, whereas MPTP decreased this specific binding only in the CA1, CA2 and CA3 of ERKOα mice. Hence, brain NMDA receptors were affected by the deletion of ERs, which affect the response to MPTP and 17β‐oestradiol treatments with brain region specificity.     

Hydrogen sulfide functions as a neuromodulator to regulate striatal neurotransmission in a mouse model of Parkinson's disease

Hydrogen sulfide (H₂S), a novel endogenous gasotransmitter, has been considered a neuromodulator to enhance hippocampal long‐term potentiation and exerts neuroprotective effects against neurotoxin‐induced neurodegeneration in rodent models of Parkinson's disease (PD). However, whether H₂S can function as a neuromodulator to regulate the levels of nigrostriatal neurotransmitters and then impact the vulnerability of dopaminergic (DA) neurons in response to neurotoxins remains unknown. For this study, we prepared a 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine plus probenecid (MPTP/p)‐induced mouse subacute model of PD to explore the modulatory effect of H₂S on monoamine and amino acid neurotransmitters in the striatum of MPTP‐treated mice. This study shows that NaHS (an H₂S donor, 5.6 mg/kg/day, i.p.) administration improves the survival rate and significantly ameliorates the weight loss of MPTP‐treated mice. NaHS treatment attenuated MPTP‐induced neuronal damage, restored the diminution of DA neurons, and suppressed the overactivation of astrocytes in the mouse striatum. Additionally, NaHS upregulated striatal serotonin levels and modulated the balance of excitatory glutamate and the inhibitory γ‐aminobutyric acid system in response to MPTP challenge. The current study indicates that H₂S may function as an effective neuromodulator to regulate striatal neurotransmission and provides insight into the potential of H₂S for PD therapy. © 2014 Wiley Periodicals, Inc.     

Combined fenobam and amantadine treatment promotes robust antidyskinetic effects in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned primate model of Parkinson's disease

Amantadine, an N‐methyl‐D‐aspartate glutamate receptor antagonist, is currently the only pharmacological treatment for levodopa‐induced dyskinesia (LID) in Parkinson's disease (PD), but causes adverse effects on the central nervous system at therapeutic doses. Fenobam, a negative modulator of metabotropic glutamate receptor subtype 5, has recently been reported to attenuate LID in MPTP‐treated macaques. The aim of the current study was to investigate the treatment interactions of fenobam and amantadine on LID in the MPTP‐treated macaque model of PD. The antidyskinetic and ‐parkinsonian effects were measured after administration of fenobam (10‐30 mg/kg) and amantadine (10‐30 mg/kg) alone and in combination. Fenobam (30 mg/kg) and amantadine (30 mg/kg) alone reduced LID, whereas lower doses of either drug did not cause any significant effects. A combined treatment of fenobam and amantadine at subthreshold doses (10 and 20 mg/kg) significantly reduced LID without worsening PD disability. These data suggest that a low‐dose combination of fenobam and amantadine can be used for alleviating dyskinesia without causing adverse motor effects. Such combined therapies may offer a new therapeutic strategy for treatment of LID in PD patients. © 2014 International Parkinson and Movement Disorder Society     

Fos expression in response to dopamine D3‐preferring phenylpiperazine drugs given with and without cocaine

WC 44 and WC 10 are phenylpiperazines with low (23 fold) to moderate (42 fold) selectivity for dopamine D3 receptors (D3Rs) over D2Rs, respectively. WC 44 is a full D3R agonist in the forskolin‐stimulated adenylyl cyclase (AC) assay, whereas WC 10 has little efficacy. In contrast to their opposite effects in the AC assay, these drugs often produce similar behavioral effects, suggesting that the AC assay does not predict the efficacy of these drugs in vivo. Here, we examined whether Fos protein expression induced by these drugs would be more consistent with their behavioral effects in vivo. Rats received either vehicle, WC 10 (5.6 mg/kg, i.p.), WC 44 (10.0 mg/kg, i.p), cocaine (10.0 mg/kg, i.p.), or cocaine with WC 10 (5.6 mg/kg, i.p.) or with WC 44 (10.0 mg/kg, i.p). Locomotion was monitored for 90 min and the brains were harvested for immunohistochemistry. Both WC 10 and WC 44 decreased spontaneous and cocaine‐induced locomotion. Both compounds also increased Fos expression relative to saline in the dorsal striatum and nucleus accumbens core and shell, and relative to cocaine alone in the nucleus accumbens shell. The findings suggest that even though these compounds have different efficacy in the AC bioassy, they produce similar brain activation and attenuation of cocaine hyperlocomotion. Together with our previous research demonstrating that these compounds down‐shift the cocaine self‐administration dose‐effect function, the findings support the idea that D3R‐selective compounds may be useful for cocaine dependence medications development. Synapse 67:847–855, 2013 . © 2013 Wiley Periodicals, Inc.     

7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced ATP loss in the mouse striatum

The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is dependent upon the MAO-B (monoamine oxidase type B)-catalyzed production of 1-methyl-4-phenylpyridinium ion (MPP(+)) and is likely to involve a perturbation of energy metabolism. Protection against MPTP neurotoxicity has been shown by treating mice with 7-nitroindazole (7-NI), a reversible inhibitor of both MAO-B and neuronal nitric oxide synthase (nNOS) activity. The objective of the present study was to evaluate (i) the relationship between the neuroprotective effect of 7-NI and MPTP-induced energy deficiency, and (ii) the role of nitric oxide production as a potential mechanism for energy perturbation after MPTP exposure. Maximum protection against striatal dopamine depletion and nigral neuronal loss was achieved when 7-NI (50 mg/kg, i.p.) was administered to C57BL/6 mice immediately before and after MPTP (50 mg/kg, s.c.). This short-term regimen of 7-NI administration parallels the time when MPTP exposure causes energy failure. 7-NI also completely prevented the loss of striatal ATP that occurs in mice during the initial hours after MPTP administration. In contrast, N(G)-nitro-L-arginine (two injections of 50 mg/kg each, given i.p. 20 and 4 h prior to MPTP), another NOS inhibitor, failed to affect MPTP-induced ATP depletion. Taken together, data indicate that (i) a temporal and causal relationship exists between the neuroprotective effect of 7-NI and its ability to counteract ATP reduction, and (ii) MAO-B rather than NOS inhibition is the mechanism by which 7-NI counteracts MPTP-induced ATP depletion.     

Poly(ADP‐ribose)polymerase inhibitor can attenuate the neuronal death after 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurotoxicity in mice

An excessive expression of poly(ADP‐ribose)polymerase (PARP) has been demonstrated to play a key role in the pathogenesis of Parkinson's disease (PD). Here we investigated the therapeutic effect of the PARP inhibitor benzamide against 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) neurotoxicity in mice. In our HPLC and Western blot analysis, pretreatment with benzamide showed a neuroprotective effect against MPTP neurotoxicity in mice. Posttreatment with benzamide also attenuated MPTP neurotoxicity in mice. Furthermore, our immunohistochemical study showed that posttreatment with benzamide significantly prevented neuronal damage by suppressing overexpression of neuronal, microglial, and astroglial PARP after MPTP treatment. These findings have important implications for the therapeutic time window and choice of PARP inhibitors in PD patients. Our present findings provide further evidence that PARP inhibitor may offer a novel therapeutic strategy for PD. © 2009 Wiley‐Liss, Inc.     

Effects of MK-801 on recognition and neurodegeneration in an MPTP-induced Parkinson's rat model

Several years after the diagnosis of Parkinson's disease (PD), 20-30% of PD patients develop dementia, known as Parkinson's disease dementia (PDD), the features of which include impairment of short-term memory and recognition function. Hyperactivation of the glutamatergic system is implicated in the neurodegeneration seen in PD. The aim of this study was to determine the effects of MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, on short-term memory and object recognition in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat animal model. MPTP was injected stereotaxically into the substantia nigra pars compacta (SNc) of male Wistar rats, then, starting 1 day later (day 1), the rats were injected daily with MK-801 (0.2 mg/kg/day, i.p.) and rats underwent a bar test on days 1-7, a T-maze test on days 8-10, and object recognition test on days 12-14. On day 1, the animals showed motor dysfunction, which recovered to control levels on day 7. MPTP-lesioned rats showed impairment of working memory in the T-maze test and of recognition in the object recognition test, both of which were prevented by MK-801 treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area were all improved by MK-801 treatment. These results suggest that NMDA receptors are involved in PD-related neuronal and behavioral dysfunction.     

甲苯四氢吡啶抑制单胺氧化酶B免疫反应的区域特征

应用免疫组织化学方法研究甲苯四氢吡啶（ＭＰＴＰ）对单胺氧化酶Ｂ的作用。单胺氧化酶Ｂ被认为可使ＭＰＴＰ转化为甲苯吡啶（ＭＰＰ＋ ）,而ＭＰＰ＋ 是损毁黑质致密部神经元的细胞毒性物质。在猫腹腔注射ＭＰＴＰ导致选择性的抑制中缝核神经元内的单胺氧化酶Ｂ免疫反应,分布显示中缝吻侧完全被抑制,而尾侧仅存少量免疫染色非常弱的神经元。但是ＭＰＴＰ对下丘脑及各脑区星状胶质细胞内的单胺氧化酶Ｂ无任何作用。这些作用伴随黑质多巴胺能神经元的丢失,但中缝核的细胞数量和形态以及５－羟色胺（５－ＨＴ）免疫组织化学反应与对照组相同。根据上述结果我们认为,ＭＰＴＰ抑制中缝核内单胺氧化酶Ｂ,但不破坏５－ＨＴ能神经元,并且中缝核内单胺氧化酶Ｂ在ＭＰＴＰ导致黑质损伤的过程中不起关键作用。     

The effect of striatal pre‐enkephalin overexpression in the basal ganglia of the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson's disease

The midbrain dopamine (DA) cell death underlying Parkinson's disease (PD) is associated with upregulation of pre‐enkephalin (pENK) in striatopallidal neurons. Our previous results obtained with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) parkinsonian monkeys suggest that increased striatal expression of pENK mRNA is a compensatory mechanism to alleviate PD‐related motor symptoms. In this study, we tested the hypothesis that increased pENK expression in the striatum protects against the neurotoxic insults of MPTP in mice. To this end, recombinant adeno‐associated virus serotype 2 also containing green fluorescent protein was used to overexpress pENK prior to DA depletion. Our results showed that overexpression of pENK in the striatum of MPTP mice induced: (i) increased levels of the opioid peptide enkephalin (ENK) in the striatum; (ii) higher densities of ENK‐positive fibers in both the globus pallidus (GP) and the substantia nigra; (iii) higher locomotor activity; and (iv) a higher density of striatal tyrosine hydroxylase‐positive fibers in the striatum. In addition, striatal overexpression of pENK in MPTP ‐treated mice led to 52 and 43% higher DA concentrations and DA turnover, respectively, in the GP compared to sham‐treated MPTP mice. These observations are in agreement with the idea that increased expression of pENK at an early stage of disease can improve PD symptoms.     

Two‐year,randomized, controlled study of safinamide as add‐on to levodopa in mid to late Parkinson's disease

In a 6‐month double‐blind, placebo‐controlled study of Parkinson's disease patients with motor fluctuations, safinamide 50 and 100 mg/d significantly increased ON‐time without increasing dyskinesia. Further long‐term safinamide use in these patients was evaluated over an additional 18 months. Patients continued on their randomized placebo, 50, or 100 mg/d safinamide. The primary endpoint was change in Dyskinesia Rating Scale total score during ON‐time over 24 months. Other efficacy endpoints included change in ON‐time without troublesome dyskinesia, changes in individual diary categories, depressive symptoms, and quality of life measures. Change in Dyskinesia Rating Scale was not significantly different in safinamide versus placebo groups, despite decreased mean total Dyskinesia Rating Scale with safinamide compared with an almost unchanged score in placebo. Ad hoc subgroup analysis of moderate to severe dyskinetic patients at baseline (36% of patients) showed a decrease with safinamide 100 mg/d compared with placebo (P = 0.0317). Improvements in motor function, activities of daily living, depressive symptoms, clinical status, and quality of life at 6 months remained significant at 24 months. Adverse events and discontinuation rates were similar with safinamide and placebo. This 2‐year, controlled study of add‐on safinamide in mid‐to‐late Parkinson's disease with motor fluctuations, although not demonstrating an overall difference in dyskinesias between patients and controls, showed improvement in dyskinesia in patients at least moderately dyskinetic at baseline. The study additionally demonstrated significant clinical benefits in ON‐time (without troublesome dyskinesia), OFF‐time, activities of daily living, motor symptoms, quality of life, and symptoms of depression. © 2014 International Parkinson and Movement Disorder Society     

Neuroprotection by sodium salicylate against 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced neurotoxicity

The potent dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) is known to produce hydroxyl radicals (OH) in vitro and in vivo. Salicylate (SA) can hydroxylate itself to form 2,3- and 2,5-dihydroxybenzoic acid (DHBA) by utilizing OH. In the present study we investigated the OH scavenging action and neuroprotective effects, if any, of SA in mice treated with MPTP (30 mg/kg i.p. twice, 16 h apart). MPTP treatment resulted in in vivo generation of OH and nigral neuronal insult as evidenced by dopamine depletion in nucleus caudatus putamen (NCP). This also caused significant decrease in glutathione in substantia nigra (SN) and NCP. SA administration alone in mice did not affect total monoamine oxidase (MAO) or MAO-B activities of the mitochondrial fraction or the crude enzyme preparation from SN or NCP. Pre-treatment of these animals with SA (25-100 mg/kg, i.p.) resulted in dose-dependent production of 2,3- and 2,5-DHBA in NCP. SA administration prior to or following MPTP blocked the neurotoxin-induced behavioural dysfunction as well as glutathione and dopamine depletion on the 7th day indicating its potent neuroprotective action. The present study suggests that SA acts as a free radical scavenger in the brain and indicates its strength as a valuable neuroprotectant.     

A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson's disease patients

Safinamide is an α-aminoamide with both dopaminergic and nondopaminergic mechanisms of action evaluated as an add-on to dopamine agonist (DA) therapy in early-stage PD. In this 24-week, double-blind study, patients with early PD receiving a stable dose of a single DA were randomized to once-daily safinamide 100 mg, safinamide 200 mg, or placebo. The primary efficacy variable was UPDRS part III (motor examination) total score. Analysis was hierarchical: 200 mg of safinamide versus placebo was tested first; the success of safinamide 100 mg versus placebo was contingent on this. Two hundred sixty-nine patients received safinamide 100 mg (n = 90), safinamide 200 mg (n = 89), or placebo (n = 90); 70, 81, and 81 patients, respectively, completed the study. Mean improvements from baseline to week 24 in UPDRS III total scores were -3.90 for safinamide 200 mg, -6.0 for safinamide 100 mg and -3.60 for placebo. The difference between safinamide 200 mg and placebo was not significant [point estimate: -0.4; 95% confidence interval (CI): -2.3-1.4; P = 0.6504]. Although the difference between 100 mg/day and placebo was significant (point estimate: -1.9; 95% CI: -3.7 to -0.1; P = 0.0419), these results are considered exploratory. No clinically meaningful differences from placebo were observed for any safety variables. This study did not demonstrate a significant improvement of the primary endpoint for safinamide 200 mg/day. Exploratory analysis of the primary endpoint for 100 mg/day demonstrated that the addition of safinamide to a stable dose of DA improves motor symptoms in early PD and warrants further investigation.     

Effect of pulsatile administration of levodopa on dyskinesia induction in drug‐naïve MPTP‐treated common marmosets: Effect of dose,frequency of administration,and brain exposure

Levodopa (L ‐dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine hydrochloride (MPTP) ‐treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L ‐dopa dose and frequency of administration on dyskinesia initiation in drug‐naïve, MPTP‐treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low‐dose of L ‐dopa with the peripheral catechol‐O‐methyltransferase inhibitor (COMT‐I), entacapone. Pulsatile administration of a low (dose range, 5.0–7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L ‐dopa plus carbidopa b.i.d. produced a dose‐related reversal of motor deficits. Repeated administration of low and high doses of L ‐dopa for 26 days to drug‐naïve, MPTP‐treated animals also caused a dose‐related induction of peak‐dose dyskinesia. Repeated administration of high‐dose L ‐dopa b.i.d. compared to once daily caused a frequency‐related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak‐dose dyskinesia. Administration of low‐dose L ‐dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L ‐dopa alone, but with no obvious change in duration of L ‐dopa's effect. However, combining entacapone with L ‐dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L ‐dopa alone. Importantly, increasing pulsatile exposure of brain to L ‐dopa by preventing its peripheral breakdown also increases dyskinesia induction. © 2003 Movement Disorder Society     

MPTP potentiates 3-nitropropionic acid-induced striatal damage in mice: reference to striatonigral degeneration

Striatonigral degeneration (SND) is a parkinsonian disorder due to the combined degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and striatal output neurons. The aims of this study were to explore (1) the behavioral and histopathological consequences of combined MPTP plus 3-nitropropionic acid (3-NP) intoxication in C57/Bl6 mice and (2) its ability to reproduce the neuropathological hallmarks of SND. 3-NP was administered i.p. every 12 h (total dose=450 mg/kg in 9 days) and MPTP i.p. at 10 mg/(kg day) (total dose=90 mg/kg in 9 days). Four groups of mice (n=10) were compared: control, 3-NP alone, MPTP alone, MPTP + 3-NP. Mice intoxicated with 3-NP and MPTP + 3-NP developed motor symptoms, including hindlimb dystonia and clasping, truncal dystonia and impaired balance adjustments. The severity of motor disorder was worse and lasted longer in MPTP + 3-NP-treated mice compared to 3-NP alone, MPTP alone and controls. 3-NP and MPTP + 3-NP-treated mice also displayed altered gait patterns, impaired motor performance on the pole test, rotarod and traversing a beam tasks and activity parameters. Several of these sensorimotor deficits were also more severe and lasted longer in MPTP + 3-NP-treated mice. Histology demonstrated increased neuronal loss along with astrocytic activation (glial fibrillary acid protein, GFAP) and a higher incidence of circumscribed striatal lateral lesions in MPTP + 3-NP-treated mice compared to 3-NP. Neuronal loss and astrocytic activation were increased in the lateral part of the striatum in 3-NP-intoxicated mice while observed both in the medial and lateral part in MPTP + 3-NP-intoxicated mice. There was also a significant loss of SNc dopaminergic neurons and striatal terminals, similar to that in MPTP-treated mice. Altogether, these results suggest that MPTP potentiates striatal damage and behavioral impairments induced by 3-NP intoxication in mice and constitutes a useful model of the motor disorder and its histopathological correlates in SND.