Irreversible Monoamine oxidase-B Inhibitor Research Articles

Rasagiline Withdrawal Syndrome in Parkinson's Disease.

Parkinson’s disease (PD) patients using dopamine agonists can develop withdrawal symptoms, referred to as dopamine agonist withdrawal syndrome (DAWS), under dose tapering or discontinuation of these drugs. DAWS includes a severe stereotypical cluster of psychiatric and psychological symptoms encompassing severe mood and anxiety disturbances, autonomic symptoms, as well as generalized pain and drug cravings. However, symptoms of withdrawal of dopamine replacement therapies (DRT) are not simply limited to dopamine agonists tapering, as observed in PD patients on deep brain stimulation after dopaminergic drugs withdrawal related to surgery. To date, no DRT-related withdrawal syndrome has been described in PD patients who discontinue rasagiline, an irreversible inhibitor of monoamine oxidase-B (MAO-B). Here we report three PD patients who developed a severe withdrawal syndrome after rasagiline suspension. The syndrome was mainly characterized by prominent psychiatric disorders (depression, anxiety with panic attacks, dysphoria, and agitation) associated with fatigue, generalized pain, and autonomic manifestations (closely resembling symptoms of DAWS). In our opinion, this report suggests the importance of closely monitoring PD patients undergoing rasagiline suspension for withdrawal symptoms and provides interesting points of reflection on the role of rasagiline and other MAO-B inhibitors in mood disorders.

KDS2010, a Newly Developed Reversible MAO-B Inhibitor, as an Effective Therapeutic Candidate for Parkinson\u2019s Disease

Monoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson’s disease (PD); however, previous clinical studies on currently available irreversible MAO-B inhibitors have yielded disappointing neuroprotective effects. Here, we tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD. We designed and synthesized a series of α-aminoamide derivatives and found that derivative KDS2010 exhibited the highest potency, specificity, reversibility, and bioavailability (> 100%). In addition, KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates. KDS2010 could be a next-generation therapeutic candidate for PD.

Detection of l-Methamphetamine and l-Amphetamine as Selegiline Metabolites.

Selegiline (SE) is a selective, irreversible monoamine oxidase-B inhibitor, used for reducing symptoms in early-stage Parkinson's disease. The metabolites of SE include l-methamphetamine, l-amphetamine and desmethylselegiline (DSE). The stereoisomers of SE metabolites, d-methamphetamine and d-amphetamine are highly addictive psychostimulants and some of the most abused drugs in South Korea. In order to differentiate medical SE users form illicit methamphetamine abusers, it is important to distinguish between the l-isomers and d-isomers in urine samples. A 52-year-old male, seemingly under the influence of intoxication and demonstrating abnormal behavior, was reported to the police. The initial urine test using a methamphetamine detection kit demonstrated a positive result. Given the initial results, the police officer requested a further analysis of the urine sample. The urine sample was screened using headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS). Both methamphetamine and amphetamine were detected, in addition to SE and DSE. To quantitate methamphetamine and amphetamine by HS-SPME-GC-MS, we performed a standard addition method due to the matrix effect of the case sample. Consistent with previous studies, our results indicated that the ratio of amphetamine to methamphetamine was 0.27, which was in the range of SE ingestion. Furthermore, we confirmed l-methamphetamine and l-amphetamine by chiral derivatization using (R)-(-)-α-methoxy-α-(trifluoromethyl) phenylacetyl chloride.

Rasagiline antiremodeling action after myocardial infarction may be mediated by circadian rhythm and neurotrophic related gene expression changes

Rasagiline mesylate (RG) is a potent, selective, irreversible monoamine oxidase-B inhibitor, developed to prolong the action of dopamine in the brain. It may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by the mitochondria permeability transition pore. We have previously shown that it decreases post-experimental infarct remodeling (REM). We investigated whether this cardioprotective result could be due to centrally mediated actions. In a rat model undergoing experimental myocardial infarction (MI) by a permanent ligation of the left anterior descending coronary artery. RG was administered, intraperitoneally for 28 days (2 mg/kg) starting 24 hours after MI induction. Treatment with RG significantly ameliorated cardiac REM echocardiographically as we have previously shown. In order to identify potential new cardioprotective mechanisms of RG action after MI, a comparative RNA expression analysis of remote region cardiac tissue was performed in placebo (Normal saline- NS), RG and Sham samples. RNA-seq analysis results were also confirmed by real time PCR. Our analysis showed: – differential RNA expression of circadian rhythm in NS samples versus RG. Circadian related genes Per3, Ciart, Dbp, Hpd, Nr1d2, and Rev-erb were upregulated while Arntl gene was downregulated (all P < 0.01); – as regards neurotrophic genes, neuropeptide Y (Npy) and neurogranin (Nrgn) genes were downregulated in RG samples compared to NS while the Brain-Derived Neurotrophic Factor (Bdnf) was upregulated (all P < 0.01). Our findings indicate that MI injury influences in a protective manner the expression of circadian rhythm and neurotrophic factor genes in cardiac tissue; potential regulation of these genes is part of the novel cardioprotective mechanism of RG action described, further advocating the possible use of this drug post-MI.

Pharmacokinetics of monoamine oxidase B inhibitors in Parkinson’s disease: current status

ABSTRACTIntroduction: Brain function depends considerably on the neurotransmission of biogenic monoamines. Their metabolism employs monoamine oxidase-B in neuronal and glial cells. Inhibition of monoamine oxidase-B elevates biogenic amine levels. Accordingly, monoamine oxidase-B inhibitors provide a symptomatic effect via dopamine on motor symptoms in patients with Parkinson’s disease.Areas covered: This narrative review aims to describe the pharmacokinetic characteristics of the available reversible and irreversible monoamine oxidase B inhibitors for the treatment of Parkinson’s disease in daily practice. All these compounds are administered on a daily basis.Expert opinion: Reversibility or irreversibility of available monoamine oxidase-B inhibition is not relevant, due to their daily intake and half-life in clinical practice. Irreversible monoamine oxidase-B inhibitors slowed the progression of neuronal dying in experimental models of Parkinson’s disease. In patients, concomitant inhibition of monoamine oxidase-B caused less increase of levodopa dosages over five years. The curve of levodopa increment diverged from the placebo curve. This reduced need for L-dopa monotherapy may be discussed as an indirect biomarker for disease severity and reflects a disease-modifying effect. In case of a symptomatic effect only, parallel curves would have occurred. Long-term L-dopa treatment should be combined with monoamine oxidase-B inhibitors when tolerated by patients.

Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease.

Monoamine oxidase-B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer's disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC50 = 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.

Rasagiline, an inhibitor of MAO-B, decreases colonic motility through elevating colonic dopamine content.

Dopamine (DA) is a negative modulator of gut motility. Monoamine oxidase-B (MAO-B) is an important metabolic enzyme degrading DA. Rasagiline, an irreversible MAO-B inhibitor, is used to treat Parkinson's disease because of its neuroprotective effect and increasing central DA. However, it is unclear whether MAO-B exists in the colon and rasagiline increases colonic DA, thereby affecting colonic motility. Immunohistochemistry, western blotting, enzyme activity assay, colonic motility recording, gut transit test, and high-performance liquid chromatography-electrochemical detection were employed in this study. Monoamine oxidase-B was distributed in the colonic muscular layers including neurons and glias of rat and human. When oral treatment of rats with rasagiline for 4weeks, in vitro colonic motility was significantly reduced, but it was greatly reversed by SCH-23390, an antagonist of DA D1 receptor. The rasagiline-treated rats also manifested decreased MAO-B activity and increased DA content in the colonic muscular layer, but no alterations were detected in the protein expressions of D1 and D2 receptors, and MAO-A and MAO-B, as well as in the content of 5-hydroxytryptamine and noradrenaline. Moreover, acute administration of rasagiline did not affect the colonic motility in vitro and the colonic DA level in rats, although MAO-B activity was significantly inhibited. Monoamine oxidase-B is abundant in the colonic muscular layer including myenteric plexus of rat and human. Long-term administration of rasagiline can increase colonic DA thereby inhibiting colonic motility, suggesting that colonic MAO-B could be a potential drug target for colonic dysmotility.

Efficacy and safety of adjunctive rasagiline in Japanese Parkinson's disease patients with wearing-off phenomena: A phase 2/3, randomized, double-blind, placebo-controlled, multicenter study

IntroductionRasagiline, a selective, irreversible monoamine oxidase-B inhibitor, is in development in Japan as adjunctive therapy to levodopa. This Phase 2/3 trial evaluated the efficacy and safety of adjunctive rasagiline in Japanese patients with Parkinson's disease (PD) and wearing-off phenomena. MethodsPatients aged 30–79 years with diagnosed PD and stable levodopa use were randomized 1:1:1 to rasagiline (0.5/1 mg/day) or placebo for 26 weeks. The primary endpoint was change from baseline in mean daily OFF-time during the treatment period. ResultsIn total, 141, 134, and 129 patients were randomized to placebo, rasagiline 0.5 mg, or rasagiline 1 mg, respectively. Baseline characteristics were well balanced. Least squares (LS) mean differences vs. placebo for change from baseline in mean daily OFF-time were −0.84 h (rasagiline 1 mg/day) and −0.60 h (rasagiline 0.5 mg/day); both differences were statistically significant. LS mean differences vs. placebo for change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II and Part III total scores (in ON-state) and Parkinson's Disease Questionnaire-39 Summary Index Score were: −1.27, −1.74, and −2.51 (0.5 mg/day) and −1.27, −2.14, and −3.84 (1 mg/day); all statistically significant. Treatment-emergent adverse events (TEAEs) occurred in 50.4/69.9/73.6% of the placebo, 0.5 mg/day, and 1 mg/day groups, respectively (most common TEAEs were nasopharyngitis [9.2/18.0/14.7%] and dyskinesia [7.1/8.3/16.3%]). ConclusionsAs an adjunct to levodopa, rasagiline reduced OFF-time and improved PD symptoms/signs (MDS-UPDRS scores) and quality of life in Japanese patients with PD and wearing-off phenomena. No important safety concerns were raised.

Simultaneous determination of MAO-A and -B activity following first time intake of an irreversible MAO-B inhibitor in patients with Parkinson's disease.

We determined monoamine oxidase-A (plasma) and -B (platelets) enzyme activity in chronic levodopa treated patients with Parkinson's disease after first time intake of an irreversible monoamine oxidase-B inhibitor. One patient received 10mg selegiline and eleven patients took 1mg rasagiline. A significant decrease of monoamine oxidase-B activity appeared 2 and 4h following monoamine oxidase-B inhibitor intake in comparison to baseline. We confirm with this design, that rasagiline and selegiline inhibit monoamine oxidase-B but not monoamine oxidase-A after single dosing.

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction.

AimRasagiline mesylate (N‐propargyl‐1 (R)‐aminoindan) (RG) is a selective, potent irreversible inhibitor of monoamine oxidase‐B with cardioprotective and anti‐apoptotic properties. We investigated whether it could be cardioprotective in a rat model undergoing experimental myocardial infarction (MI) by permanent ligation of the left anterior descending coronary artery.Methods and resultsRG was administered, intraperitoneally, for 28 days (2 mg/kg) starting 24 h after MI induction. Echocardiography analysis revealed a significant reduction in left ventricular end‐systolic and diastolic dimensions and preserved fractional shortening in RG‐treated compared with normal saline group at 28 days post‐MI (31.6 ± 2.3 vs. 19.6 ± 1.8, P < 0.0001), respectively. Treatment with RG prevented tissue fibrosis as indicated by interstitial collagen estimation by immunofluorescence staining and hydroxyproline content and attenuated the number of apoptotic myocytes in the border zone (65%) as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Caspase 3 relative protein levels were significantly decreased in the non‐infarcted myocardium. Markedly decreased malondialdehyde levels in the border zone indicate a reduction in tissue oxidative stress.ConclusionsOur study demonstrates a positive effect of RG in the post‐MI period with a significant attenuation in cardiac remodelling.

The MAO-B inhibitor deprenyl reduces the oral tremor and the dopamine depletion induced by the VMAT-2 inhibitor tetrabenazine

Tetrabenazine (TBZ) is prescribed for the treatment of chorea associated with Huntington’s disease. Via inhibition of the vesicular monoamine transporter (VMAT-2), TBZ blocks dopamine (DA) storage and depletes striatal DA; this drug also has been shown to induce Parkinsonian motor side effects in patients. Recently, TBZ was shown to induce tremulous jaw movements (TJMs) in rats and mice. TJMs are an oral tremor that has many of the characteristics of Parkinsonian tremor in humans. The present study focused upon the ability of the well-estabilished antiparkinsonian agent deprenyl to attenuate the behavioral and neurochemical effects of 2.0mg/kg TBZ. Deprenyl is a selective and irreversible inhibitor of monoamine oxidase-B, and administration of deprenyl produced a dose-related suppression of TBZ-induced TJMs. A second experiment employed in vivo microdialysis to examine extracellular DA levels in the ventrolateral striatum, the neostriatal region most closely associated with the production of TJMs, after administration of TBZ and deprenyl. Consistent with the behavioral data, TBZ alone produced a biphasic effect on extracellular DA, with an initial increases followed by a prolonged decrease during the period in which TJMs are displayed. Co-administration of deprenyl with TBZ increased DA levels compared to rats treated with TBZ alone. These results provide support for use of TBZ as a rodent model of Parkinsonism, and future studies should utilize this model to evaluate putative anti-Parkinsonian agents.

Effect of long-term treatment with rasagiline on cognitive deficits and related molecular cascades in aged mice

The present study aimed to investigate the protective effects of prolonged treatment with the selective, irreversible monoamine oxidase-B inhibitor, novel anti-parkinsonian drug, rasagiline (Azilect) in aged animals. Our findings from behavioral experiments demonstrated that long-term treatment of aged mice with rasagiline (0.2 mg/kg) exerted significant beneficial effects on mood-related dysfunction and spatial learning and memory functions. At this dose of rasagiline, chronic drug administration significantly inhibited monoamine oxidase-B activity and caused an increase in striatal dopamine and serotonin levels, while decreasing their metabolism. In addition, rasagiline treatment elevated striatal mRNA expression levels of dopamine receptors D1 and D2. Furthermore, we found that rasagiline upregulated expression levels of the synaptic plasticity markers brain-derived neurotrophic factor, tyrosine kinase-B receptor, and synapsin-1, increased Bcl-2 to Bax antiapoptotic ratio and the activity of the antioxidant enzyme, catalase in brain of aged mice. The present study demonstrated that long-term treatment with rasagiline could affect behavioral deficits in aged mice and upregulate various neuroprotective parameters in the aging brain, indicating that the drug may have therapeutic potential for treatment of age-associated neurodegenerative disorders.

Selegiline Reverses Aβ25–35-Induced Cognitive Deficit in Male Mice

Alzheimer's disease (AD) is biochemically characterized by the occurrence of extracellular deposits of amyloid beta peptide (Aβ) and intracellular deposits of the hyperphosphorylated tau protein, which are causally related to the pathological hallmarks senile plaques and neurofibrillary tangles. Monoamine oxidase B (MAO-B) activity, involved in the oxidation of biogenic monoamines, is particularly high around the senile plaques and increased in AD patients in middle to late clinical stages of the disease. Selegiline is a selective and irreversible MAO-B inhibitor and, although clinical trials already shown the beneficial effect of selegiline on cognition of AD patients, its mechanism of action remains to be elucidated. Therefore, we first investigated whether selegiline reverses the impairment of object recognition memory induced by Aβ25-35 in mice, an established model of AD. In addition, we investigated whether selegiline alters MAO-B and MAO-A activities in the hippocampus, perirhinal and remaining cerebral cortices of Aβ25-35-injected male mice. Acute (1 and 10 mg/kg, p.o., immediately post-training) and subchronic (10 mg/kg, p.o., seven days after Aβ25-35 injection and immediately post-training) administration of selegiline reversed the cognitive impairment induced by Aβ25-35 (3 nmol, i.c.v.). Acute administration of selegiline (1 mg/kg, p.o.) in combination with Aβ25-35 (3 nmol) decreased MAO-B activity in the perirhinal and remaining cerebral cortices. Acute administration of selegiline (10 mg/kg, p.o.) decreased MAO-B activity in hippocampus, perirhinal and remaining cerebral cortices, regardless of Aβ25-35 or Aβ35-25 treatment. MAO-A activity was not altered by selegiline or Aβ25-35. In summary, the current findings further support a role for cortical monoaminergic transmission in the cognitive deficits observed in AD.

Involvement of monoamine oxidase B on models of postoperative and neuropathic pain in mice

In this study we assessed the involvement of monoamine oxidase B (MAO-B), a key enzyme implicated in monoamine metabolism, on postoperative (plantar incision) and neuropathic (partial sciatic nerve ligation) pain models in mice. Paw incision submitted mice showed a significant decrease in mechanical threshold compared with the sham-operated mice, characterizing the development of mechanical allodynia. The selective and irreversible MAO-B inhibitor selegiline, at a dose sufficient to selectively inhibit MAO-B activity (10mg/kg), showed an anti-allodynic effect from 0.5 to 6h after incision. Likewise, partial sciatic nerve ligation submitted mice also developed mechanical allodynia, which was reversed by selegiline (10mg/kg) from 2 to 6h after treatment. In addition, a significant increase on striatal MAO-B activity was observed in neuropathic mice compared with the sham-operated animals, which was reversed by selegiline treatment. Taken together, our results showed that MAO-B seems to exert a critical role in the development of postoperative and neuropathic pain.

The effects of rivastigmine plus selegiline on brain acetylcholinesterase, (Na+,&amp;nbsp;K+)-, Mg2+-ATPase activities, antioxidant status, and learning performance of aged rats

We investigated the effects of rivastigmine (a cholinesterase inhibitor) and selegiline ((-)deprenyl, an irreversible inhibitor of monoamineoxidase-B), alone and in combination, on brain acetylcholinesterase (AChE), (Na(+), K(+))-, Mg(2+)-ATPase activities, total antioxidant status (TAS), and learning performance, after long-term drug administration in aged male rats. The possible relationship between the biochemical and behavioral parameters was evaluated. Aged rats were treated (for 36 days) with rivastigmine (0.3 mg/kg rat/day ip), selegiline (0.25 mg/kg rat/day im), rivastigmine plus selegiline in the same doses and way of administration as separately. Aged and adult control groups received NaCl 0.9% 0.5 ml ip. TAS was lower in aged than in adult rats, rivastigmine alone does not affect TAS, decreases AChE activity, increases (Na(+), K(+))-ATPase and Mg(2+)-ATPase activity of aged rat brain and improves cognitive performance. Selegiline alone decreases free radical production and increases AChE activity and (Na(+), K(+))-ATPase activity, improving cognitive performance as well. In the combination: rivastigmine seems to cancel selegiline action on TAS and AChE activity, while it has additive effect on (Na(+), K(+))-ATPase activity. In the case of Mg(2+)-ATPase selegiline appears to attenuate rivastigmine activity. No statistically significant difference was observed in the cognitive performance. Reduced TAS, AChE activity and learning performance was observed in old rats. Both rivastigmine and selesiline alone improved performance, although they influenced the biochemical parameters in a different way. The combination of the two drugs did not affect learning performance.

Comparison of neuroprotective and neurorestorative capabilities of rasagiline and selegiline against lactacystin‐induced nigrostriatal dopaminergic degeneration

Nigrostriatal neurodegeneration in Parkinson's disease (PD) has been postulated to be caused by various pathological conditions, such as mitochondrial defects, oxidative stress, and ubiquitin-proteasome system (UPS) dysfunction. Pharmacological strategies designed to interfere with these pathological pathways may effectively counteract the degeneration. Rasagiline and selegiline are selective and irreversible monoamine oxidase-B inhibitors that possess significant protective properties on dopamine neurons in various pre-clinical models of PD. In the present study, the neuroprotective and neurorestorative effects of rasagiline and selegiline were compared in an animal model of PD produced by inhibition of the UPS. C57BL/6 male mice were microinjected bilaterally with UPS inhibitor lactacystin (1.25 mug/side), into the medial forebrain bundle. Administration of rasagiline (0.2 mg/kg, i.p. once per day) or selegiline (1 mg/kg, i.p. once per day), started 7 days before or after (up to 28 days) after lactacystin microinjection. We found that both rasagiline and selegiline exerted a significant neuroprotective effect against lactacystin-induced neurodegeneration; but only rasagiline managed to restore the nigrostriatal degeneration. Furthermore, rasagiline showed a modest protection against lactacystin-induced inhibition of proteasomal activity. Our study indicates that compared with selegiline, rasagiline is more potent in protecting neurodegeneration induced by UPS impairment and may, therefore, exert disease-modifying effects in PD.

P.5.007 Perspectives of the use of a new antioxidant mexidol in the treatment of Parkinson's disease

Tetrabenazine (TBZ) is prescribed for the treatment of chorea associated with Huntington’s disease. Via inhibition of the vesicular monoamine transporter (VMAT-2), TBZ blocks dopamine (DA) storage and depletes striatal DA; this drug also has been shown to induce Parkinsonian motor side effects in patients. Recently, TBZ was shown to induce tremulous jaw movements (TJMs) in rats and mice. TJMs are an oral tremor that has many of the characteristics of Parkinsonian tremor in humans. The present study focused upon the ability of the well-estabilished antiparkinsonian agent deprenyl to attenuate the behavioral and neurochemical effects of 2.0 mg/kg TBZ. Deprenyl is a selective and irreversible inhibitor of monoamine oxidase-B, and administration of deprenyl produced a dose-related suppression of TBZ-induced TJMs. A second experiment employed in vivo microdialysis to examine extracellular DA levels in the ventrolateral striatum, the neostriatal region most closely associated with the production of TJMs, after administration of TBZ and deprenyl. Consistent with the behavioral data, TBZ alone produced a biphasic effect on extracellular DA, with an initial increases followed by a prolonged decrease during the period in which TJMs are displayed. Co-administration of deprenyl with TBZ increased DA levels compared to rats treated with TBZ alone. These results provide support for use of TBZ as a rodent model of Parkinsonism, and future studies should utilize this model to evaluate putative anti-Parkinsonian agents.

Pharmacological Aspects of (-)-Deprenyl

Deprenyl, the selective irreversible inhibitor of monoamine oxidase-B (MAO-B), has been synthesised as a potential antidepressant, however, due to its dopamine potentiating capacity, became a registered drug in the treatment of Parkinson's disease. Deprenyl possesses a wide range of pharmacological activities; some of them are not related to its MAO-B inhibitory potency. Beside its dopamine potentiating effect, it renders protection against a number of dopaminergic, cholinergic and noradrenergic neurotoxins with a complex mechanism of action. By inducing antioxidant enzymes and decreasing the formation of reactive oxygen species, deprenyl is able to combat an oxidative challenge implicated as a common causative factor in neurodegenerative diseases. In a dose substantially lower than required for MAO-B inhibition (10(-9)-10(-13) M), deprenyl interferes with early apoptotic signalling events induced by various kinds of insults in cell cultures of neuroectodermal origin, thus protecting cells from apoptotic death. Deprenyl requires metabolic conversion to a hitherto unidentified metabolite to exert its antiapoptotic effect, which serves to protect the integrity of the mitochondrion by inducing transcriptional and translational changes. Pharmacokinetic and metabolism studies have revealed that deprenyl undergoes intensive first pass metabolism, and its major metabolites also possess pharmacological activities. The ratio of the parent compound and its metabolites reaching the systemic circulation and the brain are highly dependent on the routes of administration. Therefore, in the treatment of neurodegenerative diseases, reconsideration of the dosing schedule, by lowering the dose of deprenyl and choosing the most appropriate route of administration, would diminish undesired adverse effects, with unaltered neuroprotective potency.

Neuroprotective and neurotoxic effects of monoamine oxidase-B inhibitors and derived metabolites under ischemia in PC12 cells

Selegiline and rasagiline are selective and irreversible monoamine oxidase-B inhibitors that exert neuroprotective effects in various preclinical models. The aim of the present study was to examine the effect of selegiline and its major metabolite, l-methamphetamine in comparison to rasagiline and its major metabolite, 1- R-aminoindan on oxygen–glucose deprivation induced cell death in nerve growth factor (NGF)-differentiated pheochromocytoma (PC12) cells. Our results show that selegiline reduces oxygen–glucose deprivation induced cell death by 30%. When the cultures were treated with rasagiline at similar concentrations, cell death induced by oxygen–glucose deprivation was reduced by 45–55%. l-methamphetamine, a major selegiline metabolite, but not 1- R-aminoindan, the major rasagiline metabolite, enhanced oxygen–glucose deprivation-induced cell death by 70%. Under normoxic conditions, both metabolites lack neurotoxicity. Concomitant exposure of the cultures under oxygen–glucose deprivation, to a combination of either selegiline and l-methamphetamine or rasagiline and 1- R-aminoindan, indicated that l-methamphetamine, but not 1- R-aminoindan, blocked the neuroprotective effect of the parental drug. These results suggest there may be a neuroprotective advantage of rasagiline over selegiline.

Activation of I(2)-imidazoline receptors enhances supraspinal morphine analgesia in mice: a model to detect agonist and antagonist activities at these receptors.

This work investigates the receptor acted upon by imidazoline compounds in the modulation of morphine analgesia. The effects of highly selective imidazoline ligands on the supraspinal antinociception induced by morphine in mice were determined. 2. Intracerebroventricular (i.c.v.) or subcutaneous (s.c.) administration of ligands selective for the I(2)-imidazoline receptor, 2-BFI, LSL 60101, LSL 61122 and aganodine, and the non selective ligand agmatine, increased morphine antinociception in a dose-dependent manner. Neither moxonidine, a mixed I(1)-imidazoline and alpha(2)-adrenoceptor agonist, RX821002, a potent alpha(2)-adrenoceptor antagonist that displays low affinity at I(2)-imidazoline receptors, nor the selective non-imidazoline alpha(2)-adrenoceptor antagonist RS-15385-197, modified the analgesic responses to morphine. 3. Administration of pertussis toxin (0.25 microg per mouse, i.c.v.) 6 days before the analgesic test blocked the ability of the I(2)-imidazoline ligands to potentiate morphine antinociception. 4. The increased effect of morphine induced by I(2)-imidazoline ligands (agonists) was completely reversed by idazoxan and BU 224. Identical results were obtained with IBI, which alkylates I(2)-imidazoline binding sites. Thus, both agonist and antagonist properties of imidazoline ligands at the I(2)-imidazoline receptors were observed. 5. Pre-treatment (30 min) with deprenyl, an irreversible inhibitor of monoamine oxidase B (IMAO-B), produced an increase of morphine antinociception. Clorgyline, an irreversible IMAO-A, given 30 min before morphine did not alter the effect of the opioid. At longer intervals (24 h) a single dose of either clorgyline or deprenyl reduced the density of I(2)-imidazoline receptors and prevented the I(2)-mediated potentiation of morphine analgesia. 6. These results demonstrate functional interaction between I(2)-imidazoline and opioid receptors. The involvement of G(i)-G(o) transducer proteins in this modulatory effect is also suggested.