Antiglutamatergic Agents Research Articles

The Endocannabinoid System in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition characterised by the selective loss of motor neurons from the spinal cord, brainstem and motor cortex. Although the pathogenic mechanisms that underlie ALS are not yet fully understood, there is significant evidence that several neurotoxic mechanisms including excitotoxicity, inflammation and oxidative stress, all contribute to disease pathogenesis. Furthermore, recent results have established that although primarily a motor neuron specific disorder, ALS is not cell-autonomous and non-neuronal cells including astroglia and microglia play a critical role in mechanism of disease. Currently the only licensed therapy available for the treatment of ALS is the anti-glutamatergic agent Riluzole, which has limited therapeutic effects. However, there is increasing evidence that cannabinoids and manipulation of the endocannabinoid system may have therapeutic value in ALS, in addition to other neurodegenerative conditions. Cannabinoids exert anti-glutamatergic and anti-inflammatory actions through activation of the CB(1) and CB(2) receptors, respectively. Activation of CB(1) receptors may therefore inhibit glutamate release from presynaptic nerve terminals and reduce the postsynaptic calcium influx in response to glutamate receptor stimulation. Meanwhile, CB(2) receptors may influence inflammation, whereby receptor activation reduces microglial activation, resulting in a decrease in microglial secretion of neurotoxic mediators. Finally, cannabinoid agents may also exert anti-oxidant actions by a receptor-independent mechanism. Therefore the ability of cannabinoids to target multiple neurotoxic pathways in different cell populations may increase their therapeutic potential in the treatment of ALS. Recent studies investigating this potential in models of ALS, in particular those that focus on strategies that activate CB(2) receptors, are discussed in this review.

The Role of the Glutamatergic System in Posttraumatic Stress Disorder

Antiglutamatergic agents, such as lamotrigine, have been used successfully for the treatment of posttraumatic stress disorder (PTSD). They could be potentially acting through the stabilization of the corticotropin-releasing factor (CRF) systems. Glutamate mediates CRF release in various brain regions involved in the pathophysiology of PTSD, antiglutamatergic agents could stabilize the CRF system and, thereby, improve the symptom complex of PTSD (reexperiencing, hyperarousal, and avoidance). The role of glutamate and CRF in PTSD and other anxiety disorders are still being elucidated. However, it is clear that the glutamatergic systems play a role in the pathophysiology of PTSD.

Is Compulsive Hoarding a Genetically and Neurobiologically Discrete Syndrome? Implications for Diagnostic Classification

Although standard diagnostic classifications consider obsessive-compulsive disorder (OCD) to be a single diagnostic entity, it has become clear that it is a heterogeneous disorder, with great variability in clinical presentation. This heterogeneity has complicated the interpretation of clinical, neurobiological, and genetic studies in OCD. Therefore, researchers have sought to identify clinically meaningful phenotypes that might be more homogeneous and heritable to facilitate our understanding of the etiology and pathophysiology of OCD and ultimately lead to improved treatments (1). Factor analytic studies have consistently identified four principal OCD symptom dimensions: 1) harm-related, aggressive, sexual, and religious obsessions with checking compulsions; 2) symmetry obsessions with arranging and repeating compulsions; 3) contamination obsessions with cleaning compulsions; and 4) hoarding and saving symptoms (1, 2). These symptom factors are relatively stable over time and show different patterns of genetic inheritance, age at onset, comorbidity, and treatment response (see 1 for review). Cluster analyses, which seek to identify mutually exclusive, categorical subgroups, indicate that some of these symptom factors, such as hoarding, may constitute discrete subtypes of OCD (3, 4). Hoarding is defined as the acquisition of and inability to discard items, even though they appear (to others) to have no value (5). Hoarding behavior has been observed in several neuropsychiatric disorders, including schizophrenia, dementia, eating disorders, autism, and mental retardation, as well as in non-clinical populations, but it is most commonly found in OCD (6). 30% to 40% of OCD patients report hoarding and saving symptoms (6–8), and about 10% to 15% have hoarding as their most prominent symptom factor (3, 6). Compulsive hoarding is most commonly driven by obsessional fears of losing important items that the patient believes will be needed later, distorted beliefs about the importance of possessions, excessive acquisition, and exaggerated emotional attachments to possessions (5). Compulsive hoarding and saving leads to clutter that can cover living and work spaces, rendering them unusable. Hoarding frequently causes significant impairment in social and occupational functioning. In severe cases, it can produce health risks from infestations, falls, fires, and inability to cook or eat in the home (6). In this issue of the Journal, Jack Samuels, Ph.D., et al. report results from the OCD Collaborative Genetics Study, finding “suggestive” linkage of compulsive hoarding to a marker on chromosome 14 in families with OCD. The linkage became stronger when only families with two or more family members with compulsive hoarding were tested. Compulsive hoarding is well known to run in families. Hoarding behaviors are significantly more prevalent in the relatives of hoarding OCD patients than nonhoarding OCD patients (9). In the OCD Collaborative Genetics Study, hoarding was the most strongly familial of the OCD symptom factors, with robust correlations among sibling pairs (10). Only two previous genetic studies have examined the hoarding phenotype. Lochner et al. (8) found that the met/met (L/L) genotype of the catechol O-methyltransferase val158met polymorphism on chromosome 22q11 was significantly more prevalent in Afrikaner OCD patients with

Is Compulsive Hoarding a Genetically and Neurobiologically Discrete Syndrome? Implications for Diagnostic Classification

Is Compulsive Hoarding a Genetically and Neurobiologically Discrete Syndrome? Implications for Diagnostic Classification

Beneficial Effects of the Antiglutamatergic Agent Riluzole in a Patient Diagnosed With Trichotillomania

Article AbstractBecause this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text.Sir: Trichotillomania is an impulse control disorder characterized by compulsive hairpulling. While the incidence of hairpulling is quite high in some populations, full criteria for trichotillomania are met by less than 1% of the population.1-3 Severe cases can lead to bald patches and marked social disability.

Is Compulsive Hoarding a Genetically and Neurobiologically Discrete Syndrome? Implications for Diagnostic Classification

Although standard diagnostic classifications consider obsessive-compulsive disorder (OCD) to be a single diagnostic entity, it has become clear that it is a heterogeneous disorder, with great variability in clinical presentation. This heterogeneity has complicated the interpretation of clinical, neurobiological, and genetic studies in OCD. Therefore, researchers have sought to identify clinically meaningful phenotypes that might be more homogeneous and heritable to facilitate our understanding of the etiology and pathophysiology of OCD and ultimately lead to improved treatments (1). Factor analytic studies have consistently identified four principal OCD symptom dimensions: 1) harm-related, aggressive, sexual, and religious obsessions with checking compulsions; 2) symmetry obsessions with arranging and repeating compulsions; 3) contamination obsessions with cleaning compulsions; and 4) hoarding and saving symptoms (1, 2). These symptom factors are relatively stable over time and show different patterns of genetic inheritance, age at onset, comorbidity, and treatment response (see 1 for review). Cluster analyses, which seek to identify mutually exclusive, categorical subgroups, indicate that some of these symptom factors, such as hoarding, may constitute discrete subtypes of OCD (3, 4). Hoarding is defined as the acquisition of and inability to discard items, even though they appear (to others) to have no value (5). Hoarding behavior has been observed in several neuropsychiatric disorders, including schizophrenia, dementia, eating disorders, autism, and mental retardation, as well as in non-clinical populations, but it is most commonly found in OCD (6). 30% to 40% of OCD patients report hoarding and saving symptoms (6–8), and about 10% to 15% have hoarding as their most prominent symptom factor (3, 6). Compulsive hoarding is most commonly driven by obsessional fears of losing important items that the patient believes will be needed later, distorted beliefs about the importance of possessions, excessive acquisition, and exaggerated emotional attachments to possessions (5). Compulsive hoarding and saving leads to clutter that can cover living and work spaces, rendering them unusable. Hoarding frequently causes significant impairment in social and occupational functioning. In severe cases, it can produce health risks from infestations, falls, fires, and inability to cook or eat in the home (6). In this issue of the Journal, Jack Samuels, Ph.D., et al. report results from the OCD Collaborative Genetics Study, finding “suggestive” linkage of compulsive hoarding to a marker on chromosome 14 in families with OCD. The linkage became stronger when only families with two or more family members with compulsive hoarding were tested. Compulsive hoarding is well known to run in families. Hoarding behaviors are significantly more prevalent in the relatives of hoarding OCD patients than nonhoarding OCD patients (9). In the OCD Collaborative Genetics Study, hoarding was the most strongly familial of the OCD symptom factors, with robust correlations among sibling pairs (10). Only two previous genetic studies have examined the hoarding phenotype. Lochner et al. (8) found that the met/met (L/L) genotype of the catechol O-methyltransferase val158met polymorphism on chromosome 22q11 was significantly more prevalent in Afrikaner OCD patients with

Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by loss of motor neurons. The cause of disease is unknown other than in the rare cases of familial disease arising from mutations in the superoxide dismutase 1 gene. Many theories for pathogenesis have been proposed - including oxidative stress, excitotoxicity, mitochondrial dysfunction and abnormal protein aggregation - based on studies of human post mortem tissue, research on animal models, and in vitro work. Here we review the evidence for the main pathogenic mechanisms and outline how they might interact to cause motor neuron death. Clinical trials have as yet failed to identify any truly effective therapies in ALS, with only riluzole providing a modest improvement in survival. Ongoing trials are exploring the value of antiglutamatergic agents, including the cephalosporin antibiotic ceftriaxone, as well as antioxidants, mitochondrial enhancers and anti-apoptotic drugs. It is likely that effective therapy will involve combinations of agents acting on different mechanisms. Gene therapy with neurotrophic factors will soon be in clinical trials, while work on stem cell therapy remains preclinical. In addition to finding effective therapies, research also needs to identify early disease markers because therapy is likely to be of most benefit when given early in the course of disease.

Delayed amnesic syndrome after riluzole autointoxication in Huntington disease

No treatment has been shown effective in slowing Huntington disease (HD). However, the anti-glutamatergic agent riluzole has been shown to reduce chorea.1,2 Therefore, trials have been performed to study the effect of riluzole on progression of HD. In the European Huntington’s Disease Initiative (EHDI) trial, patients were treated with 50 mg of riluzole (or placebo) BID. Side effects included general asthenia, nausea, and elevated serum transaminase levels. Less frequently, abdominal discomfort, dizziness, headaches, acute hepatitis, and neutropenia were noted.1,3 Little is known about the effects of riluzole overdose; both methemoglobinemia and an amnesic syndrome have been reported only once each.4,5 We present a woman who developed an amnesic syndrome 4 days after ingestion of 3 g of riluzole. A 44-year-old woman who had been diagnosed with HD in 2000 presented at the emergency room in March 2003 after ingestion of 60 tablets of study medication (riluzole, after …

Scopolamine and MK801-induced working memory deficits in rats are not reversed by CBD-rich cannabis extracts

Smoking marijuana causes working and short-term memory deficits, an effect that is mediated by cannabinoid receptor (CB 1) activation in the brain. While this may be due to the main psychoactive constituent Δ 9-tetrahydrocannabinol (Δ 9-THC), plant extracts also contain other cannabinoid and terpenoid compounds with unknown properties. Towards this end, we have recently shown that high concentrations of plant extracts rich in cannabidiol (CBD) can reverse working memory deficits induced by Δ 9-THC which is a remaining contaminant of this extract [Fadda P, Robinson L, Fratta W, Pertwee RG, Riedel G. Differential effects of THC- and CBD-rich cannabis-extracts on working memory in rats. Neuropahrmacology 2004;47:1170–9]. Since this effect was dose-dependent and indicative of memory enhancing qualities of the CBD-rich extract, this prompted a wider investigation into the effects of CBD on other forms of amnesia in order to determine the mechanism of action and to reveal its potency against anticholinergic and antiglutamatergic agents. We employed a spatial delayed matching to position task in the open-field water maze. Both scopolamine (0.2 mg/kg i.p.) and dizocilpine (MK801: 0.1 mg/kg i.p.) impaired working memory at delays of 30 s and 4 h. Two doses of CBD-rich extracts (5 and 10 mg/kg), which did not affect working memory when given alone, were unable to reverse these deficits when co-administered with scopolamine or MK801. These data suggest that reversal of working memory deficits by CBD-rich extracts are specific to the cannabinoid system and do not compensate for acutely induced cholinergic or glutamatergic receptor hypoactivity.

Glutamate-Modulating Drugs as Novel Pharmacotherapeutic Agents in the Treatment of Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that produces significant morbidity. The introduction of serotonin reuptake inhibitors in the 1980s represented an important advance in the treatment of OCD. However, few patients show complete remission of their symptoms, and some patients show minimal improvement with existing treatments. We review current treatment strategies and initial data supporting the efficacy of glutamate modulating agents as a novel class of pharmaceuticals for the treatment of OCD. Functional neuroimaging studies repeatedly reported metabolic hyperactivity in the cortico-striato-thalamo-cortical circuitry in patients with OCD. Recent magnetic resonance spectroscopy studies provide evidence of elevated glutamate levels in several brain regions in patients suffering from OCD. These findings raised the possibility that agents that reduce glutamate hyperactivity or its consequences in the CNS might be efficacious as novel therapeutic interventions. Indeed, initial evidence from our group suggests that the antiglutamatergic agent riluzole (Rilutek), which was developed for the treatment of amyotrophic lateral sclerosis, is effective in treatment-resistant OCD. Case reports suggest that other agents that modulate glutamatergic activity may likewise be effective. This new application of glutamate modulating agents holds promise for the treatment of this disabling and often inadequately treated disease.

Open-Label Trial of Riluzole in Generalized Anxiety Disorder

There is a need to identify novel pharmacotherapies for anxiety disorders. The authors examined the safety and efficacy of riluzole, an antiglutamatergic agent, in adult outpatients with generalized anxiety disorder. In an 8-week, open-label, fixed-dose study, 18 medically healthy patients with DSM-IV generalized anxiety disorder received treatment with riluzole (100 mg/day) following a 2-week drug-free period. The primary efficacy measure was the Hamilton Anxiety Rating Scale (HAM-A) score at endpoint. Twelve of the 15 patients who completed the trial responded positively to riluzole. At 8 weeks, eight of the 15 patients had HAM-A score indicating remission of their anxiety. The median time to response was 2.5 weeks. Riluzole appears to be an effective, well-tolerated, and rapidly acting anxiolytic medication for some patients with generalized anxiety disorder. Larger, placebo-controlled studies are indicated.

Beyond Monoamines: Glutamatergic Function in Mood Disorders

The monoamine theory has implicated abnormalities in serotonin and norepinephrine in the pathophysiology of major depression and bipolar illness and contributed greatly to our understanding of mood disorders and their treatment. Nevertheless, some limitations of this model still exist that require researchers and clinicians to seek further explanation and develop novel interventions that reach beyond the confines of the monoaminergic systems. Recent studies have provided strong evidence that glutamate and other amino acid neurotransmitters are involved in the pathophysiology and treatment of mood disorders. Studies employing in vivo magnetic resonance spectroscopy have revealed altered cortical glutamate levels in depressed subjects. Consistent with a model of excessive glutamate-induced excitation in mood disorders, several antiglutamatergic agents, such as riluzole and lamotrigine, have demonstrated potential antidepressant efficacy. Glial cell abnormalities commonly associated with mood disorders may at least partly account for the impairment in glutamate action since glial cells play a primary role in synaptic glutamate removal. A hypothetical model of altered glutamatergic function in mood disorders is proposed in conjunction with potential antidepressant mechanisms of antiglutamatergic agents. Further studies elucidating the role of the glutamatergic system in the pathophysiology of mood and anxiety disorders and studies exploring the efficacy and mechanism of action of antiglutamatergic agents in these disorders, are likely to provide new targets for the development of novel antidepressant agents.

The Role of Newer Antiglutamatergic Agents as Mood-Stabilizers in Bipolar Disorder

In bipolar patients, maintenance treatment with anticonvulsive agents is a valid alternative to lithium. These agents have widely varying mechanisms of action. Some of these medications focus on the current understanding of antiglutamatergic mechanisms of action and their treatment implications for bipolar disorders.

Riluzole improves motor deficits and attenuates loss of striatal neurons in a sequential double lesion rat model of striatonigral degeneration (parkinson variant of multiple system atrophy)

We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA approved for disease-modifying therapy in amyotrophic lateral sclerosis (ALS), in an established double lesion rat model of striatonigral degeneration (SND), the neuropathological substrate of parkinsonism associated with MSA (MSA-P). Riluzole was administered prior to and consecutively for ten days following double lesion placement in the left-sided medial forebrain bundle and ipsilateral striatum. Assessment of motor behaviour using a flex field system showed a significant reduction of motor disturbance in animals with striatonigral lesions treated with riluzole compared to lesioned but untreated animals (P<0.001). DARPP-32 immunohistochemistry revealed a significant reduction of absolute striatal lesion volume in riluzole treated animals compared to lesioned but untreated animals (P<0.01). No significant difference in counts of nigral dopaminergic neurons was found in treated versus untreated double-lesioned animals. The results of our study indicate that riluzole mediates neuroprotective effects in the double lesion rat model of MSA-P. Whether riluzole also protects autonomic and cerebellar pathways that are frequently affected in MSA remains to be determined. Nonetheless, our study is the first to provide an experimental rationale for exploring possible neuroprotective effects of riluzole in MSA.

Failure of caspase inhibition in the double-lesion rat model of striatonigral degeneration (multiple system atrophy)

In the present study we assessed the neuroprotective effects of the pan-caspase inhibitor z-VAD.fmk [N-benzyloxycarbony-valine-alanine-aspartate-(OMe)-fluoromethylketone], and the caspase-3 inhibitor Ac-DEVD.CHO (acetyl-aspartate-chloromethylketone) in the double-lesion rat model of striatonigral degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). Male Wistar rats were divided into three groups, receiving either Ac-DEVD.CHO, z-VAD.fmk or normal saline before lesion surgery, comprising a sequential unilateral quinolinic acid (QA) lesion of the striatum followed by a 6-hydroxydopamine (6-OHDA) lesion of the ipsilateral medial forebrain bundle. At 2 weeks post lesion, all rats underwent testing of spontaneous nocturnal locomotor behavior in an automated Photobeam Activity System (FlexField). Immunohistochemistry was performed with tyrosine hydroxylase, dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein and glial fibrillary acidic protein antibodies. Morphometry was performed using computerized image analysis. Behavioral and morphological analysis failed to show striatal or nigral protection in caspase inhibitor-treated animals. Our findings suggest that anti-apoptotic strategies are unrewarding in the SND rat model and, therefore, alternative neuroprotective interventions such as anti-glutamatergic agents or inhibitors of microglial activation should be explored instead.

Riluzole Augmentation for Treatment-Resistant Depression

Back to table of contents Previous article Next article Letter to the EditorFull AccessRiluzole Augmentation for Treatment-Resistant DepressionGERARD SANACORA, M.D., Ph.D., STEVEN F. KENDELL, M.D., LISA FENTON, Psy.D., VLADIMIR CORIC, M.D., and JOHN H. KRYSTAL, M.D., GERARD SANACORASearch for more papers by this author, M.D., Ph.D., STEVEN F. KENDELLSearch for more papers by this author, M.D., LISA FENTONSearch for more papers by this author, Psy.D., VLADIMIR CORICSearch for more papers by this author, M.D., and JOHN H. KRYSTALSearch for more papers by this author, M.D., New Haven, Conn.Published Online:1 Nov 2004https://doi.org/10.1176/appi.ajp.161.11.2132AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Glutamate is implicated in the pathophysiology and treatment of mood disorders (1). The following case reports pertain to the use of riluzole, a putative antiglutamatergic agent indicated for the treatment of amyotrophic lateral sclerosis, as add-on therapy for treatment-resistant major depressive disorder.Ms. A was a 42-year-old woman with a history of major depressive disorder. Despite pharmacotherapy strategies, including fluoxetine, fluoxetine augmented with lithium, and her current regimen of bupropion (100 mg b.i.d.) and venlafaxine (up to 300 mg/day), she remained depressed, with scores of 21 on the 25-item Hamilton Depression Rating Scale and 17 on the Beck Depression Inventory. After we obtained written informed consent, riluzole, 50 mg b.i.d., was added to her current medication regimen. Within 1 week, her Hamilton depression scale and Beck Depression Inventory scores decreased by 16 and 10 points, respectively. Repeated measures of her depression severity reflected scores in the remitted range, with a score of 1 on the Hamilton depression scale and 0 on the Beck Depression Inventory at the end of 6 weeks and a Hamilton depression scale score of 4 and a Beck Depression Inventory score of 4 at the end of 12 weeks of continued treatment.Ms. B was a 55-year-old woman with a 33-year history of major depressive disorder. Her pharmacotherapy history included adequate courses of various tricyclic and selective serotonin reuptake inhibitor monotherapies, nefazodone, and the combination of sertraline and bupropion. Immediately after an index course of seven bifrontal ECT treatments, her Beck Depression Inventory score was 15; however, within 2 weeks, her score rose to 32 despite continued weekly ECT treatments. For the previous 6 months, while her mood was maintained with fluoxetine (80 mg/day), methylphenidate (58 mg/day), and ongoing cognitive behavior therapy, her Beck Depression Inventory scores fluctuated between 17 and 31. After we obtained written informed consent, treatment with riluzole, 50 mg b.i.d., was started. Ms. B’s Hamilton depression scale and Beck Depression Inventory scores before riluzole were 34 and 27, respectively. Within 1 week, her Hamilton depression scale score dropped to 22, and her Beck Depression Inventory score decreased to 11. At week 6, her Hamilton depression scale and Beck Depression Inventory scores were both 7; at week 12, her scores were 9 and 5, respectively.Baseline laboratory evaluations, including liver function tests and a CBC with differential, were collected before study initiation. Additional tests were performed at 2–3-week intervals for 12 weeks and then monthly to monitor riluzole’s known risk of serum aminotransferase elevations and neutropenia. Neither patient experienced significant aminotransferase elevations (more than five times the normal upper limits) or neutropenia or endorsed any other side effect.Although case studies necessitate cautious interpretation, these results are consistent with a recent finding suggesting riluzole’s effectiveness in treating depression (2) and further substantiate accruing evidence indicating that several classes of glutamatergic agents possess antidepressant properties (3).

No Magic Bullets: The Ephemeral Nature of Anesthetic-mediated Neuroprotection

No Magic Bullets: The Ephemeral Nature of Anesthetic-mediated Neuroprotection

Chronic treatment with small doses of cabergoline prevents dopa-induced dyskinesias in parkinsonian monkeys.

Levodopa continues to be the most effective agent for the symptomatic treatment of Parkinson's disease (PD). But over time, initial benefits decline in efficacy because of a rise in adverse effects such as dyskinesias. The pathophysiology of levodopa-induced dyskinesias (LID) is not completely understood, but it appears to result from deficient regulation by dopamine of corticostriatal glutamatergic inputs leading to a cascade of neurochemical changes in the striatum and the output pathways. In the present study, we examined if the addition of small doses of cabergoline (a long-acting D(2) receptor agonist) to levodopa could prevent LID. The major hypothesis is that sustained activation of postsynaptic D(2) receptors on medium spiny neurons even by small doses of cabergoline could prevent or reduce LID. The minor hypothesis, and the more controversial of the two, is that the long-acting stimulation by small doses of cabergoline could diminish the release of glutamate by the corticostriatal pathway and prevent LID. Eight MPTP-treated monkeys with a long-standing and stable parkinsonian syndrome and having never received dopaminergic agents were used. Two groups of four were treated for 1 month with levodopa/benserazide administered orally (100 mg/25 mg). The second group received in addition a threshold dose of cabergoline (dose ranging from 0.015 to 0.035 mg/kg, SC). During the treatment, we observed LID in the levodopa group but not in the group receiving levodopa+cabergoline. Furthermore, the combination produced a comparable antiparkinsonian effect in terms of quality but prolonged the duration (by 1 to 2 hours) and increased the locomotion (mean for 2 weeks congruent with 104%). Our data suggest that a small dose of a long-acting D(2) agonist combined with high doses of levodopa could be preventive of LID in patients with PD and could be an alternative to using antiglutamatergic agents for this purpose.

The antioxidant activity of caroverine

Caroverine, 1-(2-diethylaminoethyl)-3-( p-methoxy benzyl)-1,2-dihydro-2-quinoxalin-2-on-hydrochloride, is a class B calcium-channel-blocker and antiglutamatergic agent with significant effects on the brain function. Caroverine exhibits competitive AMPA antagonism, and at higher concentrations, noncompetitive NMDA antagonism. In clinical practice caroverine is used as a spasmolytic and otoneuroprotective agent. Since reactive oxygen species are supposed to be involved in the pathogenesis of inner ear diseases in which caroverine shows beneficial effects, the present study aimed to investigate the antioxidant properties of caroverine. Lipid peroxidation of liposomal membranes was suppressed in the presence of caroverine. In order to understand the mechanism of this antioxidant action of caroverine, we determined the rate constants both for a possible reaction with superoxide (O 2 −) radicals from xanthine/xanthine oxidase and for a possible reaction with hydroxyl ( OH) radicals in Fenton system. Using a defined chemical reaction model O 2 − scavenging was found to occur at a rather low rate constant only (3×10 2 M −1 s −1). Thus, a reaction of caroverine with O 2 − radicals is of marginal significance. In contrast, the reaction of caroverine with OH radicals occurs at an extremely high rate constant ( k=1.9×10 10 M −1 s −1). The strong antioxidant activity of caroverine is therefore based both on the partial prevention and highly active scavenging of hydroxyl radicals.

Molecular and Cellular Mechanism of Glutamate Receptors in Relation to Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of the central nervous system (CNS) with an unknown etiology. This disorder is characterized clinically by muscular weakness and wasting, and pathologically by selective degeneration of the corticospinal tracts and motor neurons of the brain stem and spinal cord. Median survival following onset is 3 to 5 years. Riluzole, an antiglutamatergic agent has been shown to have modest beneficial effects on survival. Glutamate is the main excitatory neurotransmitter in the CNS and excessive activation of glutamate receptors is excitotoxic to neurons. Glutamate receptor-mediated excitotoxicity has been proposed to explain the pattern of selective neuronal cell death and clinical manifestation of ALS. Activation of glutamate receptors leading to elevation of intracellular calcium may play a major role. This review will focus on the current understanding of the molecular and cellular mechanisms of glutamate receptors in relation to ALS.