ABSTRACT
Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have a severe impact on the patient's quality of life. The current review summarizes the evidence for the utility of amantadine in TBI in connection to its mechanism of action. Amantadine, the drug combining multiple mechanisms of action, may offer both neuroprotective and neuroactivating effects in TBI patients. Indeed, the use of amantadine in TBI has been encouraged by several clinical practice guidelines/recommendations. Amantadine is also available as an infusion, which may be of particular benefit in unconscious patients with TBI due to immediate delivery to the central nervous system and the possibility of precise dosing. In other situations, orally administered amantadine may be used. There are several questions that remain to be addressed: can amantadine be effective in disorders of consciousness requiring long-term treatment and in combination with drugs approved for the treatment of TBI? Do the observed beneficial effects of amantadine extend to disorders of consciousness due to factors other than TBI? Well-controlled clinical studies are warranted to ultimately confirm its utility in the TBI and provide answers to these questions.
ABSTRACT
A strong correlation has been reported between patient-reported quality of life (QoL) and the investigator-rated Disability Assessment Scale (DAS) in patients with spasticity. The current analysis evaluates the effect of incobotulinumtoxinA on QoL-related outcomes (limb position abnormality, as well as dressing- and hygiene-related disability, measured with the DAS) in adults with upper limb spasticity, using pooled data from six studies. Separate analyses for each DAS domain were performed using data from patients with disabilities for that domain (DAS score ≥1). Results showed that a significantly greater proportion of incobotulinumtoxinA-treated compared with placebo-treated patients achieved a ≥1-point reduction from baseline in each of the DAS domains (improvement) 4 weeks after the first injection. The benefits of incobotulinumtoxinA were observed regardless of the baseline severity of DAS impairment and of the time elapsed since stroke. The effects of incobotulinumtoxinA 4 weeks after injection were maintained or enhanced over multiple injection cycles for all three DAS domains, supporting the use of repeated injection cycles to provide sustained QoL benefit. IncobotulinumtoxinA represents an important treatment option to achieve better QoL-related outcomes for patients with upper limb spasticity, irrespective of the duration of their condition.
Subject(s)
Botulinum Toxins, Type A , Limb Deformities, Congenital , Adult , Humans , Quality of Life , Botulinum Toxins, Type A/therapeutic use , Muscle Spasticity/drug therapyABSTRACT
Objective: To confirm the efficacy and safety of incobotulinumtoxinA (Xeomin®, Merz Pharmaceuticals GmbH; total dose 400 U) in Japanese subjects with lower limb (LL) poststroke spasticity using the Modified Ashworth Scale spasticity score for the plantar flexors (MAS-PF). Methods: This phase III study (Japic clinical study database No. CTI-153030, 7 October 2015) included a double-blind, 12-week main period (MP) in which 208 subjects were randomized to receive one injection cycle of incobotulinumtoxinA 400 U (n = 104) or placebo (n = 104) in the pes equinus muscles, and an open-label extension (OLEX) that enrolled 202 subjects who received three injection cycles, 10-14 weeks in duration (the last cycle was fixed at 12 weeks). Changes in MAS-PF for incobotulinumtoxinA vs. placebo from baseline to Week 4 of the MP and to the end-of-cycle visits in the OLEX were evaluated. Results: The area under the curve for the change in MAS-PF was statistically significantly greater with incobotulinumtoxinA vs. placebo in the MP (mean: -7.74 vs. -4.76; least squares mean: -8.40 vs. -5.81 [p = 0.0041]). In the OLEX, mean changes in MAS-PF from baseline to end-of-study showed continued improvement with repeated injections. No new safety concerns were observed with the incobotulinumtoxinA treatment. Its efficacy and safety were consistent regardless of the length of the injection cycle interval in the OLEX. Conclusion: This study demonstrated that incobotulinumtoxinA (total dose 400 U) is an effective and a well-tolerated treatment for LL spasticity in Japanese subjects using flexible injection intervals of 10-14 weeks.
ABSTRACT
Background: Botulinum toxin type A is an effective treatment widely used to address post-stroke spasticity. Long-term repeated treatment with botulinum toxin type A may result in reduced efficacy due to the induction of neutralizing antibodies. Based on data from a phase 3 study of incobotulinumtoxinA for post-stroke upper limb spasticity, we describe the therapeutic response to botulinum toxin type A treatment in two neutralizing antibody-positive patients previously treated with other preparations of botulinum toxin type A. Case: Two patients (a 65-year-old woman and a 36-year-old woman) with post-stroke upper limb spasticity were previously treated with onabotulinumtoxinA, and neutralizing antibodies were detected in their sera at baseline using the mouse hemidiaphragm assay. After onabotulinumtoxinA had been discontinued for at least 16 weeks, incobotulinumtoxinA (400 U) was administered in three or four injection cycles. Good therapeutic responses, manifested by a reduction of 1-2 points on the modified Ashworth scale, were noted after each injection. The patients' sera remained positive for neutralizing antibodies throughout the incobotulinumtoxinA treatment period. Discussion: These patients, who were previously treated with onabotulinumtoxinA and were neutralizing antibody positive throughout the clinical study period, showed stable therapeutic responses following incobotulinumtoxinA treatment. IncobotulinumtoxinA could be initiated for patients with neutralizing antibodies induced by onabotulinumtoxinA.
ABSTRACT
OBJECTIVE: Blepharospasm is a focal dystonia whereby excessive eyelid muscle contractions cause involuntary eye closure. Botulinum neurotoxin type A (BoNT-A) injections are an approved treatment. This randomized placebo-controlled trial (NCT01896895; EudraCT number 2012-004821-26) assessed the efficacy, safety, and treatment effect duration of incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH), a BoNT-A formulation without complexing proteins, in BoNT-A-naïve adults with blepharospasm. METHODS: Subjects received incobotulinumtoxinA 50 U, 25 U (total dose) or placebo during a main study period (MP; 6-20 weeks). Patients needing a second injection received incobotulinumtoxinA ≤70 U in an open-label extension period (EP; 6-20 weeks). Treatment effect durations were time from first injection to EP injection or final MP visit and from EP injection to end-of-study visit. Times to effect onset and to waning of effect (MP) were time from injection to first subject-assessed onset effect and time from injection to subject-reported waning of effect, respectively. RESULTS: Of 61 subjects, 39 entered the EP. During the MP, median duration of treatment effect was longer with incobotulinumtoxinA 50 U (20 weeks) versus incobotulinumtoxinA 25 U (11 weeks) or placebo (6 weeks). Median duration of treatment effect was 20 weeks during the EP. Median time to effect onset was 5, 7, and 14 days with 50 U, 25 U, and placebo, respectively (p = .022 for 50 U versus placebo). Median time to waning of treatment effect was comparable between groups. CONCLUSION: Subjects reported an effect onset from 5 days after injection lasting up to 20 weeks (maximum observation period). Data indicate that incobotulinumtoxinA re-treatment of blepharospasm may not be required at fixed 12-week intervals and provide evidence for a patient-tailored approach.
PLAIN LANGUAGE SUMMARYBlepharospasm is a condition in which involuntary contractions of the eyelid muscles cause the eye to close. The condition can be treated with botulinum neurotoxin type A (BoNT-A) injections. This study assessed the duration of effect and time to onset of effect for the BoNT-A formulation incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH) in adults with blepharospasm. Subjects received a single injection of one of two doses of incobotulinumtoxinA (total dose 25 or 50 U) or placebo and received a second injection of incobotulinumtoxinA only (total dose ≤70 U; the second injection was not compared with placebo) if needed 620 weeks after the first injection. After the first injection, the median (mid-point of values from all subjects) duration of treatment effect was longer with the higher incobotulinumtoxinA dose (20 weeks) than with the lower dose (11 weeks) and was longer with both incobotulinumtoxinA doses than with placebo (6 weeks). After the second incobotulinumtoxinA injection, the median duration of treatment effect was 20 weeks. The time to onset of effect was quicker with both incobotulinumtoxinA doses (5 and 7 days for the higher and lower doses, respectively) than with placebo (14 days) and the difference was statistically significant for the higher incobotulinumtoxinA dose compared with placebo. The time to waning of treatment effect was similar for the two incobotulinumtoxinA doses and placebo. This study shows that incobotulinumtoxinA is an effective treatment for blepharospasm, with a fast onset of action. In addition, the effects of one injection can last for up to 20 weeks.
Subject(s)
Blepharospasm , Botulinum Toxins, Type A , Neuromuscular Agents , Adult , Blepharospasm/drug therapy , Double-Blind Method , Humans , Treatment OutcomeABSTRACT
The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson's disease symptoms and viral infections. Considering amantadine's affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels. Based on published clinical studies, traumatic brain injury, fatigue [e.g., in multiple sclerosis (MS)], and chorea in Huntington's disease should be regarded potential, encouraging indications. Preclinical investigations suggest amantadine's therapeutic potential in several further indications such as: depression, recovery after spinal cord injury, neuroprotection in MS, and cutaneous pain. Query in the database http://www.clinicaltrials.gov reveals research interest in several further indications: cancer, autism, cocaine abuse, MS, diabetes, attention deficit-hyperactivity disorder, obesity, and schizophrenia.
Subject(s)
Huntington Disease , Parkinson Disease , Amantadine/therapeutic use , Diamond , Humans , Receptors, N-Methyl-D-AspartateABSTRACT
This study aimed to assess the efficacy/safety of incobotulinumtoxinA (Xeomin®, Merz Pharmaceuticals GmbH) in botulinum neurotoxin-naïve subjects with blepharospasm. Botulinum neurotoxin-naïve subjects (≥ 12 months without botulinum neurotoxin treatment for blepharospasm) received single-dose incobotulinumtoxinA 50 U, 25 U, or placebo. Subjects were followed for 6-20 weeks (main period). Qualified subjects entered an open-label extension period and received another incobotulinumtoxinA injection (≤ 70 U). The primary efficacy variable was change from baseline in the Jankovic Rating Scale (JRS) severity subscore at the main period of week 6. Other efficacy variables included changes in the Blepharospasm Disability Index score and JRS frequency subscore and sumscore. Adverse events were monitored. Sixty-one subjects were randomized (main period: incobotulinumtoxinA 50 U, n = 19; incobotulinumtoxinA 25 U, n = 22; placebo, n = 20); 39 entered the open-label extension period (9, 14, and 16 subjects from the incobotulinumtoxinA 50 U, incobotulinumtoxinA 25 U, and placebo groups [main period], respectively, changed to open-label extension period dosing). A statistically significantly greater reduction in JRS severity subscore was reported for subjects receiving incobotulinumtoxinA 50 U versus placebo (ANCOVA, least square mean difference: - 1.2, p = 0.0004). Subjects receiving incobotulinumtoxinA experienced improvements in other efficacy variables versus baseline and/or placebo. Sustained clinical improvements and low adverse event rates (22.2-42.1%) were observed. This is the second placebo-controlled, double-blind study that demonstrates favorable efficacy/safety of incobotulinumtoxinA in subjects with blepharospasm. IncobotulinumtoxinA is the first botulinum neurotoxin that could fulfill the American Academy of Neurology criteria for a Level A recommendation for blepharospasm.Trial registration ClinicalTrials.gov identifier, NCT01896895.
Subject(s)
Blepharospasm , Botulinum Toxins, Type A , Neuromuscular Agents , Blepharospasm/drug therapy , Botulinum Toxins, Type A/adverse effects , Double-Blind Method , Humans , Neuromuscular Agents/adverse effects , Treatment OutcomeABSTRACT
Introduction: The safety and tolerability of incobotulinumtoxinA 400 U for upper- and lower-limb post-stroke spasticity was assessed in a small cohort of Japanese patients during the open-label lead-in tolerability periods (LITP) of two phase 3 studies (CTI-153029 and CTI-153030; Japan Pharmaceutical Information Centre).Methods: Adult patients received a single incobotulinumtoxinA injection session (total dose of 400 U) in the upper (J-PURE) or lower limb (J-PLUS). Adverse events (AEs) were assessed at 1, 4, 8 and 12 weeks post-injection during the 12 week follow-up.Results: The LITP of J-PURE and J-PLUS included 11 patients each. Mild/moderate AEs were reported by 5/11 (45.5%) and 8/11 (72.7%) patients in J-PURE and J-PLUS, respectively. No serious AEs were reported. Non-serious, transient AEs of special interest reported by two patients in J-PURE comprised muscular weakness and eyelid ptosis. No patient discontinued due to AEs.Conclusion: Preliminary results in this small population suggest that incobotulinumtoxinA 400 U is well tolerated for treating upper- or lower-limb post-stroke spasticity in Japanese patients.
Subject(s)
Botulinum Toxins, Type A/therapeutic use , Muscle Spasticity/drug therapy , Neuromuscular Agents/therapeutic use , Adult , Botulinum Toxins, Type A/adverse effects , Female , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
BACKGROUND: Upper-limb spasticity frequently occurs after stroke and there is a clinical need for more effective therapies. The Phase III J-PURE study assessed the efficacy and safety of incobotulinumtoxinA up to 400 U for post-stroke upper-limb spasticity in Japan. METHODS: In the 12-week main period (MP) of this double-blind, placebo-controlled study, Japanese subjects with upper-limb spasticity received one injection cycle of incobotulinumtoxinA 400 U, 250 U, or matching placebo. Eligible subjects enrolled in an open-label extension (OLEX) period of three injection cycles of incobotulinumtoxinA 400 U (32-40 weeks). The primary objective was to establish the efficacy of a single incobotulinumtoxinA injection using the Modified Ashworth Scale (MAS) wrist score. Secondary efficacy outcomes and safety were also assessed. RESULTS: Among 100 treated subjects, AUCs for incobotulinumtoxinA 400 and 250 U were significantly different versus placebo (p = 0.0014 and p = 0.0031, respectively) for change from baseline in MAS wrist score to the end of the MP, with similar results from baseline to week 4. IncobotulinumtoxinA 400 U was superior versus placebo across other spasticity patterns and at most study visits. Improvements were maintained throughout the OLEX period. Disability Assessment Scale and Investigator's Clinical Global Impression scores improved significantly for incobotulinumtoxinA 400 U versus placebo from baseline to week 4 (p = 0.0067 and p < 0.0001, respectively). IncobotulinumtoxinA was well tolerated up to 52 weeks, with no unexpected adverse events. CONCLUSION: IncobotulinumtoxinA reduced (pathologically) increased muscle tone, improved functionality and was well tolerated in Japanese subjects with post-stroke upper-limb spasticity.
Subject(s)
Botulinum Toxins, Type A/pharmacology , Muscle Spasticity/drug therapy , Neuromuscular Agents/pharmacology , Outcome Assessment, Health Care , Stroke/complications , Upper Extremity , Adult , Aged , Botulinum Toxins, Type A/administration & dosage , Botulinum Toxins, Type A/adverse effects , Double-Blind Method , Female , Humans , Japan , Male , Middle Aged , Muscle Spasticity/etiology , Neuromuscular Agents/administration & dosage , Neuromuscular Agents/adverse effects , Upper Extremity/physiopathologyABSTRACT
Metabotropic glutamate receptor 5 (mGluR5) is a drug target for central nervous system disorders such as fragile X syndrome that involve excessive glutamate-induced excitation. We tested the efficacy of a novel negative allosteric modulator of mGluR5 developed by Merz Pharmaceuticals, MRZ-8456, in comparison to MPEP and AFQ-056 (Novartis, a.k.a. mavoglurant) in both in vivo and in vitro assays in a mouse model of fragile X syndrome, Fmr1KO mice. The in vivo assays included susceptibility to audiogenic-induced seizures and pharmacokinetic measurements of drug availability. The in vitro assays included dose response assessments of biomarker expression and dendritic spine length and density in cultured primary neurons. Both MRZ-8456 and AFQ-056 attenuated wild running and audiogenic-induced seizures in Fmr1KO mice with similar pharmacokinetic profiles. Both drugs significantly reduced dendritic expression of amyloid-beta protein precursor (APP) and rescued the ratio of mature to immature dendritic spines. These findings demonstrate that MRZ-8456, a drug being developed for the treatment of motor complications of L-DOPA in Parkinson's disease and which completed a phase I clinical trial, is effective in attenuating both well-established (seizures and dendritic spine maturity) and exploratory biomarker (APP expression) phenotypes in a mouse model of fragile X syndrome.
Subject(s)
Excitatory Amino Acid Antagonists/therapeutic use , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Indoles/therapeutic use , Isoquinolines/therapeutic use , Phenotype , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Receptor, Metabotropic Glutamate 5/antagonists & inhibitors , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Female , Fragile X Syndrome/drug therapy , Indoles/chemistry , Indoles/pharmacology , Isoquinolines/chemistry , Isoquinolines/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Pregnancy , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Random AllocationABSTRACT
Eltoprazine, a drug that had previously been developed for aggression, has recently been investigated for L-DOPA-induced dyskinesia in animal models of Parkinson´s disease (PD) and in dyskinetic PD patients. Much less is known about effects of eltoprazine in other therapeutic indications. Indeed, the pharmacological profile of eltoprazine might suggest its effects on anxiety and food intake, but also adverse effect potential, which is the focus of the present study. Given for 2 weeks either as infusion or as twice-daily treatment, eltoprazine produced a decrease in food intake and body weight at doses leading to 200-500 nM plasma concentrations. In the elevated plus maze eltoprazine increased anxietylike behavior. On the other hand, it induced a clearcut anxiolytic effect in context fear conditioning test starting at ca. 0.3 mg/kg, and failed to produce any significant effect in fear potentiated startle test. Regarding adverse effects, eltoprazine was found to produce hypothermia starting from 1 mg/kg. At s imilar doses it also increased locomotion in the open field. However, eltoprazine failed to affect acquisition in context fear conditioning paradigm, which may indicate lack of its detrimental effect on learning at the doses tested (i.e., up to 5 mg/kg). In summary, effects of eltoprazine in different anxiety tests were equivocal while its effect on body weight seems robust and requires further investigation. It is to be determined whether these effects can be expected at the doses free of adverse effects.
Subject(s)
Anti-Anxiety Agents/therapeutic use , Anxiety/drug therapy , Appetite Depressants/therapeutic use , Body Weight/drug effects , Piperazines/therapeutic use , Analysis of Variance , Animals , Anti-Anxiety Agents/adverse effects , Anti-Anxiety Agents/blood , Anxiety/blood , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Routes , Exploratory Behavior/drug effects , Male , Piperazines/adverse effects , Piperazines/blood , Rats , Rats, Sprague-DawleyABSTRACT
MRZ-9547 (d-(2-(2-oxo-4(R)-phenylpyrrolidin-1-yl)-acetamide) is a drug acting at the dopamine transporter (DAT). In the present study, effects of MRZ-9547 alone and in combination with L-3,4-dihydroxyphenylalanine (L-DOPA) were investigated in rodent models predictive for efficacy in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). In rats pre-treated with haloperidol (0.2 mg/kg i.p.), MRZ-9547 (25-100 mg/kg i.p.) dose-dependently attenuated decrease in horizontal locomotion, activity in central zone, and rearings starting at 50 mg/kg i.p. In rats depleted of monoamines by α-methyl-p-tyrosine and reserpine treatment, MRZ-9547 attenuated hypolocomotion starting at 100 mg/kg i.p. At the doses 25-100 mg/kg i.p. the drug induced dose-dependent ipsilateral rotations in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced nigrostriatal system lesions. However, MRZ-9547 enhanced contralateral rotation produced by L-DOPA given at an effective (25 mg/kg i.p.), but not at a sub-effective (6.25 mg/kg i.p.) dose. Microdialysis experiments revealed that MRZ-9547 penetrated well to the brain and did not show any pharmacokinetic interaction with L-DOPA. In unilaterally 6-OHDA-lesioned rats having developed abnormal involuntary movements (AIMs, a rodent correlate of LID) after chronic L-DOPA treatment, MRZ-9547 (50 mg/kg i.p.) did not significantly affect the AIMs expression. The results indicate that MRZ-9547 may by itself have antiparkinsonian activity at early stages of the disease, when some dopaminergic terminals are still intact. It may also enhance antiparkinsonian effect of L-DOPA. MRZ-9547 does not seem to influence the expression of LID in 6-OHDA-lesioned rats. The results support the use of MRZ-9547 in PD patients treated with L-DOPA.
Subject(s)
Acetamides/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Parkinsonian Disorders/drug therapy , Pyrrolidinones/pharmacology , Animals , Brain/drug effects , Brain/pathology , Brain/physiopathology , Dopamine Uptake Inhibitors/adverse effects , Dose-Response Relationship, Drug , Drug Therapy, Combination , Dyskinesia, Drug-Induced/drug therapy , Dyskinesia, Drug-Induced/pathology , Dyskinesia, Drug-Induced/physiopathology , Haloperidol , Levodopa/adverse effects , Levodopa/pharmacology , Male , Motor Activity/drug effects , Oxidopamine , Parkinsonian Disorders/pathology , Parkinsonian Disorders/physiopathology , Rats, Sprague-DawleyABSTRACT
This review describes the preclinical mechanisms that may underlie the increased therapeutic benefit of combination therapy-with the N-methyl-D-aspartate receptor antagonist, memantine, and an acetylcholinesterase inhibitor (AChEI)-for the treatment of Alzheimer's disease (AD). Memantine, and the AChEIs target two different aspects of AD pathology. Both drug types have shown significant efficacy as monotherapies for the treatment of AD. Furthermore, clinical observations indicate that their complementary mechanisms offer superior benefit as combination therapy. Based on the available literature, the authors have considered the preclinical mechanisms that could underlie such a combined approach. Memantine addresses dysfunction in glutamatergic transmission, while the AChEIs serve to increase pathologically lowered levels of the neurotransmitter acetylcholine. In addition, preclinical studies have shown that memantine has neuroprotective effects, acting to prevent glutamatergic over-stimulation and the resulting neurotoxicity. Interrelations between the glutamatergic and cholinergic pathways in regions of the brain that control learning and memory mean that combination treatment has the potential for a complex influence on disease pathology. Moreover, studies in animal models have shown that the combined use of memantine and the AChEIs can produce greater improvements in measures of memory than either treatment alone. As an effective approach in the clinical setting, combination therapy with memantine and an AChEI has been a welcome advance for the treatment of patients with AD. Preclinical data have shown how these drugs act via two different, but interconnected, pathological pathways, and that their complementary activity may produce greater effects than either drug individually.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Cholinesterase Inhibitors/administration & dosage , Memantine/administration & dosage , Alzheimer Disease/pathology , Animals , Brain/drug effects , Brain/metabolism , Brain/pathology , Drug Therapy, Combination , Excitatory Amino Acid Antagonists/administration & dosage , Humans , Neuroprotective Agents/administration & dosage , Treatment OutcomeABSTRACT
Dual probe microdialysis was used to investigate whether GluN2A and GluN2B NMDA receptor subunits regulate striatal output pathways under dyskinetic conditions. The preferential GluN2A antagonist NVP-AAM077 perfused in the dopamine-depleted striatum of 6-hydroxydopamine hemilesioned dyskinetic rats reduced GABA and glutamate levels in globus pallidus whereas the selective GluN2B antagonist Ro 25-6981 elevated glutamate without affecting pallidal GABA. Moreover, intrastriatal NVP-AAM077 did not affect GABA but elevated glutamate levels in substantia nigra reticulata whereas Ro 25-6981 elevated GABA and reduced nigral glutamate. To investigate whether GluN2A and GluN2B NMDA receptor subunits are involved in motor pathways underlying dyskinesia expression, systemic NVP-AAM077 and Ro 25-6981 were tested for their ability to attenuate levodopa-induced abnormal involuntary movements. NVP-AAM077 failed to prevent dyskinesia while Ro 25-6981 mildly attenuated it. We conclude that in the dyskinetic striatum, striatal GluN2A subunits tonically stimulate the striato-pallidal pathway whereas striatal GluN2B subunits tonically inhibit striato-nigral projections. Moreover, GluN2A subunits are not involved in dyskinesia expression whereas GluN2B subunits minimally contribute to it.
Subject(s)
Corpus Striatum/metabolism , Dopamine/metabolism , Glutamic Acid/metabolism , Receptors, N-Methyl-D-Aspartate/physiology , gamma-Aminobutyric Acid/metabolism , Animals , Corpus Striatum/drug effects , Dopamine Agents/adverse effects , Dyskinesia, Drug-Induced/etiology , Globus Pallidus/drug effects , Globus Pallidus/metabolism , Glutamic Acid/drug effects , Levodopa/adverse effects , Male , Microdialysis , Neostriatum/drug effects , Neostriatum/metabolism , Oxidopamine/adverse effects , Phenols/pharmacology , Piperidines/pharmacology , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Substantia Nigra/drug effects , Substantia Nigra/metabolism , gamma-Aminobutyric Acid/drug effectsABSTRACT
The aim of the present paper was to study the effects of GABAA receptor-positive modulators (L-838417 and NS11394) showing a preference for α2/3 subunits of the GABAA receptor, in models of pain, anxiety, learning, memory and motor function. These compounds have been suggested to have a favourable therapeutic profile over nonselective compounds such as diazepam. In this study, we tested both compounds for their effects in rat models of formalin-induced pain, spinal nerve-ligation-induced mechanical allodynia, plus maze, open field, rotarod, balance beam walking, contextual fear conditioning and Morris water maze. Both compounds exerted analgesic, but no anxiolytic effects. However, they induced motor side-effects, and learning and memory impairment at similar doses. Therefore, the anxiolytic effect and the lack of side-effects of these compounds, as described in the literature, could not be confirmed in the present study.
Subject(s)
Benzimidazoles/pharmacology , Fluorobenzenes/pharmacology , GABA-A Receptor Agonists/pharmacology , Receptors, GABA-A/drug effects , Triazoles/pharmacology , Allosteric Regulation , Analgesics/administration & dosage , Analgesics/pharmacology , Analgesics/toxicity , Animals , Anxiety/drug therapy , Benzimidazoles/administration & dosage , Benzimidazoles/toxicity , Disease Models, Animal , Dose-Response Relationship, Drug , Fear , Fluorobenzenes/administration & dosage , Fluorobenzenes/toxicity , GABA-A Receptor Agonists/administration & dosage , GABA-A Receptor Agonists/toxicity , Male , Maze Learning/drug effects , Memory Disorders/chemically induced , Motor Activity , Pain/drug therapy , Pain/physiopathology , Rats , Rats, Wistar , Receptors, GABA-A/metabolism , Triazoles/administration & dosage , Triazoles/toxicityABSTRACT
Subtype 5 metabotropic glutamate receptors (mGluR5) are abundant in the basal ganglia, amygdala, septum, hippocampus, peripheral sensory neurones and dorsal horn of the spinal cord. Thus, mGluR5 has been implicated in central processes underlying movement control, emotion, learning, and nociception. Different negative allosteric modulators (NAMs) of mGluR5 were repeatedly shown to be efficacious in models of L: -DOPA-induced dyskinesia (LID), anxiety, and some forms of pain. MRZ-8676 (6,6-dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one) is a novel proprietary, selective, orally bioavailable mGluR5 NAM. MRZ-8676 (8.33, 25 and 75 mg/kg) showed a high efficacy in the rat model of LID, with the maximal effect size reaching ~80%. The antidyskinetic effects of MRZ-8676 (75 mg/kg) did not show tolerance as assessed after repetitive (6 days) treatment. MRZ-8676 (25 or 75 mg/kg) demonstrated moderate efficacy in two rat models of anxiety-contextual fear conditioning and the elevated plus maze. MRZ-8676 (25 mg/kg) was also effective in the formalin test, a rat model of persistent pain. The efficacious doses of MRZ-8676 did not produce any detrimental effects on motor performance of rats as determined by means of automated open field and rotarod. However, high doses of MRZ-8676 (75 or 150 mg/kg) disrupted learning in an aversive learning paradigm of the contextual fear conditioning test. In conclusion, MRZ-8676 is a new investigational agent with an efficacy profile similar to the widely published reference mGluR5 NAMs. The drug was demonstrated to possess a superior antidyskinetic efficacy with a sufficient therapeutic window. MRZ-8676 has also therapeutic potential as an anxiolytic and analgesic drug.
Subject(s)
Dyskinesia, Drug-Induced/drug therapy , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/therapeutic use , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Adrenergic Agents/toxicity , Allosteric Regulation/drug effects , Analysis of Variance , Animals , Brain/drug effects , Brain/metabolism , Calcium/metabolism , Cognition Disorders/drug therapy , Cognition Disorders/etiology , Conditioning, Psychological/drug effects , Disease Models, Animal , Dopamine Agents/adverse effects , Dose-Response Relationship, Drug , Dyskinesia, Drug-Induced/complications , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/pathology , Fear/drug effects , In Vitro Techniques , Levodopa/adverse effects , Male , Maze Learning/drug effects , Microdialysis , Monoamine Oxidase Inhibitors/administration & dosage , Motor Activity/drug effects , Oxidopamine/toxicity , Pain Measurement , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/drug therapy , Picolinic Acids/administration & dosage , Psychomotor Performance/drug effects , Quinolones/chemistry , Quinolones/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/metabolism , Rotarod Performance Test , Tandem Mass Spectrometry/methods , Time FactorsABSTRACT
L-DOPA remains the gold-standard treatment for Parkinson's disease but causes motor fluctuations and dyskinesia. Metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for antidyskinetic therapies. Here, we evaluate the effects of fenobam, a noncompetitive mGluR5 antagonist already tested in humans, using rodent and nonhuman primate models of Parkinson's disease. In both animal models, acute administration of fenobam attenuated the L-DOPA-induced abnormal involuntary movements (50-70% reduction at the doses of 30mg/kg in rats and 10mg/kg in monkeys). The effect consisted in a reduction of peak-dose dyskinesia, whereas the end-dose phase was not affected. Chronic administration of fenobam to previously drug-naïve animals (de novo treatment) attenuated the development of peak-dose dyskinesia without compromising the anti-parkinsonian effect of L-DOPA. In addition, fenobam prolonged the motor stimulant effect of L-DOPA. We conclude that fenobam acts similarly in rat and primate models of L-DOPA-induced dyskinesia and represents a good candidate for antidyskinetic treatment in Parkinson's disease.
Subject(s)
Dyskinesia, Drug-Induced/drug therapy , Imidazoles/therapeutic use , Levodopa/adverse effects , Parkinson Disease, Secondary/drug therapy , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Analysis of Variance , Animals , Disease Models, Animal , Dyskinesia, Drug-Induced/etiology , Female , Macaca mulatta , Male , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Rats , Rats, Sprague-DawleyABSTRACT
Systemic inhibition of complex I by rotenone in rats represents a model of Parkinson's disease (PD). The aim of this study was to elucidate whether neramexane (NMDA, nicotinic alpha9/alpha10 and 5-HT3 receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist) or 2-methyl-6-(phenyl-ethyl)-pyrimidine (MPEP, metabotropic glutamate receptor 5 antagonist) prevents rotenone-induced parkinsonian-like behaviours and neurochemical changes in rats. Rotenone (2.5 mg/kg i.p. daily) was administered over 60 days together with saline, neramexane (5 mg/kg i.p., b.i.d.), idazoxan (2.5 mg/kg i.p., b.i.d.) or MPEP (2.5 mg/kg i.p., b.i.d.). The same doses of neramexane, idazoxan and MPEP were administered to rats treated with vehicle instead of rotenone. Treatment-related effects on parkinsonian-like behaviours, such as hypokinesia/rigidity and locomotor activity, were evaluated. Moreover, concentrations of dopamine, serotonin and their metabolites were measured in rats from each experimental group. Over the 60-day treatment period, the rotenone+saline treated animals developed hypokinesia, expressed as an increase in the bar and grid descent latencies in the catalepsy test, and a decrease in locomotor activity. Neramexane and idazoxan partially prevented the development of catalepsy in rotenone-treated rats. Co-administration of MPEP with rotenone resulted only in a decrease in descent latency in the grid test on day 60. Chronic rotenone treatment reduced concentrations of dopamine and serotonin in the anterior striatum, which was blocked by co-treatment with neramexane or idazoxan but not with MPEP. Only neramexane treatment blocked the rotenone-induced decrease in dopamine levels in the substantia nigra pars compacta. In conclusion, neramexane and idazoxan counteracted to some extent the development of parkinsonian symptoms and neurochemical alterations in the rotenone model of Parkinson's disease.
Subject(s)
Adrenergic alpha-2 Receptor Antagonists , Adrenergic alpha-Antagonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Neuroprotective Agents/pharmacology , Neurotoxicity Syndromes/prevention & control , Parkinsonian Disorders/prevention & control , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Basal Ganglia/drug effects , Basal Ganglia/metabolism , Behavior, Animal/drug effects , Catalepsy/chemically induced , Catalepsy/prevention & control , Cyclopentanes/pharmacology , Disease Models, Animal , Dopamine/metabolism , Hypokinesia/chemically induced , Hypokinesia/prevention & control , Idazoxan/pharmacology , Male , Motor Activity/drug effects , Muscle Rigidity/chemically induced , Muscle Rigidity/prevention & control , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/metabolism , Neurotoxicity Syndromes/physiopathology , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/physiopathology , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5 , Receptors, Adrenergic, alpha-2/metabolism , Receptors, Metabotropic Glutamate/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Rotenone , Serotonin/metabolism , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Time FactorsABSTRACT
Kynurenic acid (KYNA) is a recognized broad-spectrum antagonist of excitatory amino acid receptors with a particularly high affinity for the glycine co-agonist site of the N-methyl-D-aspartate (NMDA) receptor complex. KYNA is also a putative endogenous neuroprotectant. Recent studies show that KYNA strongly blocks alpha7 subtype of nicotinic acetylcholine receptors (nAChRs). The present studies were aimed at assessing effects of acute and chronic nicotine exposure on KYNA production in rat brain slices in vitro and ex vivo. In brain slices, nicotine significantly increased KYNA formation at 10 mM but not at 1 or 5 mM. Different nAChR antagonists (dihydro-beta-erythroidine, methyllycaconitine and mecamylamine) failed to block the influence exerted by nicotine on KYNA synthesis in cortical slices in vitro. Effects of acute (1 mg/kg, i.p.), subchronic (10-day) and chronic (30-day) administration of nicotine in drinking water (100 microg/ml) on KYNA brain content were evaluated ex vivo. Acute treatment with nicotine (1 mg/kg i.p.) did not affect KYNA level in rat brain. The subchronic exposure to nicotine in drinking water significantly increased KYNA by 43%, while chronic exposure to nicotine resulted in a reduction in KYNA by 47%. Co-administration of mecamylamine with nicotine in drinking water for 30 days reversed the effect exerted by nicotine on KYNA concentration in the cerebral cortex. The present results provide evidence for the hypothesis of reciprocal interaction between the nicotinic cholinergic system and the kynurenine pathway in the brain.
Subject(s)
Cerebral Cortex/drug effects , Kynurenic Acid/metabolism , Nicotine/toxicity , Nicotinic Agonists/toxicity , Receptors, Nicotinic/drug effects , Administration, Oral , Animals , Cerebral Cortex/enzymology , Cerebral Cortex/metabolism , Dose-Response Relationship, Drug , Down-Regulation , Drug Administration Schedule , Injections, Intraperitoneal , Kynurenic Acid/blood , Male , Nicotine/administration & dosage , Nicotinic Agonists/administration & dosage , Nicotinic Antagonists/pharmacology , Rats , Rats, Wistar , Receptors, Nicotinic/metabolism , Transaminases/metabolismABSTRACT
L-DOPA-induced dyskinesia (LID) in Parkinson's disease has been linked to altered dopamine and glutamate transmission within the basal ganglia. In the present study, we compared compounds targeting specific subtypes of glutamate receptors or calcium channels for their ability to attenuate LID and the associated activation of striatal nuclear signaling and gene expression in the rat. Rats with 6-hydroxydopamine lesions were treated acutely or chronically with L-DOPA in combination with the following selective compounds: antagonists of group I metabotropic glutamate receptors (mGluR), (2-methyl-1,3-thiazol-4-yl) ethynylpyridine (MTEP) for mGluR5 and (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methane sulfonate (EMQMCM) for mGluR1; an agonist of group II mGluR, 1R,4R,5S,6R-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268); N-methyl-D-aspartate (NMDA)-R2B subunit (NR2B)-selective NMDA receptor antagonists 1-[2-(4-hydroxyphenoxy)ethyl]-4-[(4-methylphenyl)methyl]-4-piperidinol hydrochloride (Ro631908) and (+/-)-(R(*),S(*))-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)1-piperidine propanol (Ro256981); and an L-type calcium channel antagonist, 4-(4-benzofurazanyl)-1,-4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester (isradipine). Dyskinesia and rotarod performance were monitored during chronic drug treatment. The striatal expression of phospho-extracellular signal-regulated kinase (ERK) 1/2 and mitogen- and stress-activated kinase (MSK)-1, or prodynorphin mRNA was examined after acute or chronic treatment, respectively. In the acute treatment studies, only MTEP and EMQMCM significantly attenuated L-DOPA-induced phospho-ERK1/2 and/or phospho-MSK-1 expression, with MTEP being the most effective (70-80% reduction). In the chronic experiment, only MTEP significantly attenuated dyskinesia without adverse motor effects, whereas EMQMCM and LY379268 inhibited the L-DOPA-induced improvement in rotarod performance. The NR2B antagonist had positive antiakinetic effects but did not reduce dyskinesia. Only MTEP blocked the up-regulation of prodynorphin mRNA induced by L-DOPA. Among the pharmacological treatments examined, MTEP was most effective in inhibiting LID and the associated molecular alterations. Antagonism of mGluR5 seems to be a promising strategy to reduce dyskinesia in Parkinson's disease.