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1.
Eur J Pharmacol ; 895: 173882, 2021 Mar 15.
Article in English | MEDLINE | ID: mdl-33482180

ABSTRACT

Fabry disease (FD) is an X-linked metabolic storage disorder arising from the deficiency of lysosomal α-galactosidase A, which leads to the gradual accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), throughout the body. Pain in the extremities is an early symptom of FD; however, the underlying pathophysiological mechanisms remain unknown. α-Galactosidase A knockout animals exhibit nociceptive behaviors, with enhanced expression levels of several ion channels. These characteristics are observed in animals treated with nerve growth factor (NGF). Here, we aimed to elucidate the potential of NGF signaling as a cause of FD-associated pain, using intraplantar Gb3-treated mice displaying mechanical allodynia. Treatment with a neutralizing antibody against a precursor of NGF (proNGF) or its receptor, p75 neurotrophin receptor (p75NTR), resulted in the recovery from Gb3-induced pain. Conversely, anti-NGF and anti-tropomyosin receptor kinase A antibodies failed to exert analgesic effects. Gb3 injection had no effects on the expression levels of proNGF and p75NTR in the plantar skin and dorsal root ganglia, suggesting that Gb3 activates the pain pathway, possibly mediated through functional up-regulation of proNGF-p75NTR signaling. Furthermore, by pharmacological approaches using a protein kinase A (PKA) inhibitor and a cholesterol-removing agent, we found that p75NTR-phosphorylating PKA and lipid rafts for phosphorylated p75NTR translocation were required for Gb3-induced pain. These results suggest that acute exposure to Gb3 induces mechanical allodynia via activation of the proNGF-p75NTR pathway, which involves lipid rafts and PKA. Our findings provide new pathological insights into FD-associated pain, and suggest the need to develop therapeutic interventions targeting proNGF-p75NTR signaling.


Subject(s)
Ganglia, Spinal/metabolism , Hyperalgesia/metabolism , Nerve Growth Factor/metabolism , Pain Threshold , Protein Precursors/metabolism , Receptors, Nerve Growth Factor/metabolism , Skin/metabolism , Trihexosylceramides , Analgesics/pharmacology , Animals , Antibodies, Neutralizing/pharmacology , Cyclic AMP-Dependent Protein Kinases/metabolism , Disease Models, Animal , Ganglia, Spinal/physiopathology , Hyperalgesia/chemically induced , Hyperalgesia/physiopathology , Hyperalgesia/prevention & control , Male , Membrane Microdomains/metabolism , Mice, Inbred C57BL , Nerve Growth Factor/antagonists & inhibitors , Pain Threshold/drug effects , Protein Precursors/antagonists & inhibitors , Receptor, trkA/metabolism , Receptors, Nerve Growth Factor/antagonists & inhibitors , Signal Transduction
3.
Front Behav Neurosci ; 13: 176, 2019.
Article in English | MEDLINE | ID: mdl-31427934

ABSTRACT

In patients with Parkinson's disease (PD), non-motor symptoms (NMS) including depression and anxiety are often recognized before motor symptoms develop. Monoamine oxidase (MAO)-B inhibitors are therapeutically effective for motor symptoms; however, their effects on NMS in PD are yet to be fully assessed. Here, we aimed to explore the antidepressant-like effects of propargyl MAO-B inhibitors, selegiline and rasagiline, in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a PD model, and to elucidate the mechanisms underlying these effects. Four repeated intraperitoneal injections of MPTP at 17.5 mg/kg to C57BL/6 mice led to a partial reduction in the number of nigrostriatal tyrosine hydroxylase-positive neurons and to the extension of immobility time during the tail suspension test (TST), without any obvious induction of motor deficits. A single subcutaneous administration of selegiline at 10 mg/kg shortened the extended immobility time of MPTP mice in the TST, without any increase in motor activities, suggesting that selegiline exerts antidepressant-like effects. In this test, rasagiline did not produce antidepressant-like effects, although the inhibitory effect of 3 mg/kg rasagiline on brain MAO activity was comparable to that of 10 mg/kg selegiline. The shortened immobility time in the TST correlated with reduced cortical dopamine (DA) turnover rates in MPTP mice treated with selegiline, but not in MPTP mice treated with rasagiline. These results suggest that MAO inhibition does not entirely account for the antidepressant-like effects of selegiline. Administration of selegiline (10 mg/kg), but not rasagiline (1 mg/kg), to MPTP mice restored the impaired long-term potentiation induced by high-frequency stimulation in the medial prefrontal cortex (mPFC), and normalized the reduced phosphorylation of Ca2+/calmodulin-dependent protein kinase IIα, which is known to be involved in neuroplasticity, in the frontal cortex. In MPTP mice, the antiparkinsonian drug pramipexole (0.3 mg/kg), a DA D2 and D3 receptor agonist, that has been shown to be effective in treating depression in PD, ameliorated depression-like behavior and synaptic dysfunction in the mPFC. Taken together, the antidepressant-like effects of selegiline in MPTP mice are attributable to the restoration of impaired synaptic plasticity in the mPFC, suggesting its potential for treating depression in early PD.

4.
Behav Brain Res ; 359: 353-361, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30359642

ABSTRACT

Selegiline, an irreversible inhibitor of monoamine oxidase (MAO)-type B, is widely prescribed for Parkinson's disease and, at higher doses, for major and atypical depression, whereby it is non-selectively inhibitory to both MAO-A and MAO-B activities. MAO inhibitors have been considered to function as antidepressants through MAO-A inhibition. We have previously reported that selegiline exerts antidepressant-like effects in the mouse forced swim test (FST) via dopamine D1 receptor activation. Our objective was to elucidate the mechanisms underlying the antidepressant-like effects of selegiline. We also tested another propargylamine MAO-B inhibitor, rasagiline. Triple subcutaneous injection (at 24, 5, and 1 h prior to behavioral testing) with selegiline (10 mg/kg/injection), but not rasagiline (1, 3, or 10 mg/kg/injection), reduced the immobility time in the mouse FST and rat tail suspension test. In the hippocampus and prefrontal cortex of mice subjected to the FST, selegiline and rasagiline completely inhibited MAO-B activities. However, selegiline suppressed MAO-A activities and monoamine turnover rates at a lesser degree than rasagiline at the same doses, indicating that the antidepressant-like effects of selegiline are independent of MAO-A inhibition. Moreover, selegiline, but not rasagiline, increased the hippocampal dopamine content. A single subcutaneous administration of 10 mg/kg selegiline, but not of rasagiline, significantly prevented hippocampal CA1 long-term potentiation impairment, induced by low-frequency stimulation prior to high-frequency stimulation in rats. These results suggest that the antidepressant-like effects of selegiline are attributable to enhancement of dopaminergic transmission and prevention of the impairment of synaptic plasticity in the hippocampus.


Subject(s)
Antidepressive Agents/pharmacology , Depressive Disorder/drug therapy , Dopamine/metabolism , Hippocampus/drug effects , Neuronal Plasticity/drug effects , Selegiline/pharmacology , Animals , Corticosterone/blood , Depressive Disorder/metabolism , Dose-Response Relationship, Drug , Hippocampus/metabolism , Indans/pharmacology , Male , Mice , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/pharmacology , Neuronal Plasticity/physiology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Rats, Wistar , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Time Factors
5.
Behav Brain Res ; 347: 350-359, 2018 07 16.
Article in English | MEDLINE | ID: mdl-29526790

ABSTRACT

3,4-Dihydroxy-l-phenylalanine (l-Dopa) remains the most effective drug for treating the motor symptoms of Parkinson's disease (PD). However, its long-term use is limited due to motor complications such as wearing-off and dyskinesia. A clinical study in PD patients with motor complications has demonstrated that selegiline, a monoamine oxidase type B inhibitor, is effective in reducing off time without worsening dyskinesia, although another study has shown worsening dyskinesia. Here, using unilateral 6-hydroxydopamine-lesioned rats showing degeneration of nigrostriatal dopaminergic neurons and l-Dopa-induced motor complications, we determined the efficacy of selegiline in controlling l-Dopa-induced motor fluctuations and exacerbated dyskinesia. Repeated administration of l-Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, twice daily for 22 days) progressively shortened rotational response duration (on time) and augmented peak rotation in lesioned rats. Single subcutaneous injection of selegiline (10 mg/kg) extended l-Dopa-induced shortened on time without augmenting peak rotation. Furthermore, l-Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, once daily for 7 days) progressively increased abnormal involuntary movements (l-Dopa-induced dyskinesia, LID) and peak rotation. Single subcutaneous injection of selegiline (10 mg/kg) did not exacerbate LID or alter mRNA expression of prodynorphin (PDy) and activity-regulated cytoskeleton-associated protein (Arc), both mRNAs associated with LID in the lesioned striatum. Despite undetectable plasma concentrations of selegiline and its metabolites at 24 h post-administration, these on time and LID effects did not decrease, suggesting involvement of irreversible mechanisms. Altogether, these results indicate that selegiline is effective in increasing on time without worsening dyskinesia.


Subject(s)
Antiparkinson Agents/adverse effects , Antiparkinson Agents/pharmacology , Dyskinesia, Drug-Induced/drug therapy , Levodopa/adverse effects , Parkinsonian Disorders/drug therapy , Selegiline/pharmacology , Animals , Benserazide/adverse effects , Benserazide/pharmacology , Cytoskeletal Proteins/metabolism , Disease Models, Animal , Drug Therapy, Combination , Dyskinesia, Drug-Induced/pathology , Dyskinesia, Drug-Induced/physiopathology , Enkephalins/metabolism , Levodopa/pharmacology , Male , Movement/drug effects , Nerve Tissue Proteins/metabolism , Oxidopamine , Parkinsonian Disorders/pathology , Parkinsonian Disorders/physiopathology , Protein Precursors/metabolism , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Time Factors
6.
J Neural Transm (Vienna) ; 124(5): 519-523, 2017 05.
Article in English | MEDLINE | ID: mdl-28213761

ABSTRACT

l-Methamphetamine has been occasionally referred to as a stimulant similar to d-methamphetamine, probably owing to insufficient comparative studies. Here, we directly compared psychomotor efficacies and pharmacokinetics of methamphetamine enantiomers in mice. Only d-methamphetamine, but not l-methamphetamine, induced stereotypy and sensitization at 1-10 mg/kg. However, plasma pharmacokinetic parameters of 10 mg/kg l-methamphetamine were ≥tenfold those of 1 mg/kg d-methamphetamine. These results clearly indicate that differential psychomotor efficacies of methamphetamine enantiomers are independent of their pharmacokinetic profiles.


Subject(s)
Brain/drug effects , Central Nervous System Stimulants/pharmacology , Methamphetamine/pharmacology , Motor Activity/drug effects , Animals , Brain/metabolism , Central Nervous System Stimulants/blood , Central Nervous System Stimulants/pharmacokinetics , Dose-Response Relationship, Drug , Male , Methamphetamine/blood , Methamphetamine/pharmacokinetics , Mice , Stereoisomerism , Stereotyped Behavior/drug effects , Time Factors
7.
Metabolism ; 53(12): 1532-7, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15562395

ABSTRACT

We report here a newly synthesized cyanoimino-oxothiazolidine derivative, FPFS-410, which has properties to ameliorate both hyperglycemia and dyslipidemia. Treatment of genetically obese-diabetic db/db mice with FPFS-410 markedly ameliorates severe hyperglycemia and hypertriglyceridemia. Although the oxothiazolidine ring of FPFS-410 shares a structural similarity with other thiazolidinedione derivatives, reporter assays showed that FPFS-410 was much less potent to activate peroxisome proliferators-activated receptor gamma (PPAR gamma) as compared with pioglitazone. When 3T3-L1 preadipocytes were treated with FPFS-410, intracellular accumulation of lipids was facilitated in a similar fashion to pioglitazone. Moreover, treatment with FPFS-410 throughout the differentiation course resulted in a significant increase in glucose transport. These results suggest that FPFS-410 may provide a useful therapeutic candidate for diabetes mellitus and dyslipidemia.


Subject(s)
Adipocytes/drug effects , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/pharmacology , Thiazoles/pharmacology , 3T3-L1 Cells , Adipocytes/cytology , Adipocytes/metabolism , Animals , Biological Transport , Blood Glucose/drug effects , Blood Glucose/metabolism , Cell Differentiation/drug effects , Deoxyglucose/metabolism , Male , Mice , Mice, Inbred C57BL , Molecular Structure , PPAR gamma/agonists , PPAR gamma/genetics , PPAR gamma/metabolism , Pioglitazone , Thiazolidinediones/pharmacology , Triglycerides/blood
8.
J Pharmacol Sci ; 92(4): 428-32, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12939529

ABSTRACT

We compared the degree of neurotoxic outcome in the retina exposed to three nitric oxide (NO) donors with different half-life of NO release. Intravitreal injection of NO donors resulted in a significant decrease in cell density in the ganglion cell layer and thinning of the inner plexiform layer in a half-life time-dependent manner. Concurrent injection of an NO-trapping reagent with an NO donor abolished NO donor-induced retinal damage. (+)-MK-801 also prevented NO-induced retinal damage, indicating that N-methyl-D-aspartate receptors are partly involved in NO-induced neurodegeneration. These results may be relevant to a pathogenic role of NO - glutamate receptor in several ophthalmic disorders.


Subject(s)
Nitric Oxide Donors/toxicity , Nitric Oxide/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Retina/drug effects , Retina/pathology , Animals , Half-Life , Male , Nitric Oxide Donors/pharmacokinetics , Nitroso Compounds/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Retina/metabolism
9.
Invest Ophthalmol Vis Sci ; 44(4): 1760-6, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12657619

ABSTRACT

PURPOSE: To investigate the neurotoxic outcome in the rat retina exposed to nitric oxide (NO) released from an NO donor and to evaluate the effects of neurotrophic factors on the survival of NO-damaged retinal cells. METHODS: An NO releasing compound, N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino) ethanamine (NOC 12), was intravitreously injected into a rat's right eye. The influences of NOC 12 on retinal neurons and the neuroprotective effects of ciliary neurotrophic factor (CNTF) or brain-derived neurotrophic factor (BDNF) on NOC 12-mediated damage were estimated by counting cells in the ganglion cell layer (GCL) and by measuring the thickness of retinal layers. The exact count of retinal ganglion cells (RGCs) was also confirmed by means of retrograde labeling with a fluorescent tracer. RESULTS: Morphometric analyses of retinal damage in the NOC 12-exposed eyes demonstrated a significant and dose-dependent decrease in cell density in the GCL and a reduction in thickness of the inner plexiform layer and inner nuclear layer, but not of the outer nuclear layer. TdT-dUTP terminal nick-end labeling of retinal sections after intravitreous injection of NOC 12 demonstrated that NO could trigger apoptotic cell death. The counting of the RGCs labeled with a fluorescent tracer suggested that a decrease in GCL cell density induced by NOC 12 reflects a loss in RGCs. Treatment with CNTF (1 microg) or BDNF (1 microg) before the intravitreous injection of NOC 12 (400 nmol) demonstrated that these trophic factors have protective effects against NO-induced neuronal cell death in the retina. CONCLUSIONS: Exogenous NO induces retinal neurotoxicity, suggesting that NO plays a pathogenic role in degenerative retinal diseases. BDNF and CNTF protect retinal neurons from NO-mediated neurotoxicity.


Subject(s)
Brain-Derived Neurotrophic Factor/pharmacology , Ciliary Neurotrophic Factor/pharmacology , Neuroprotective Agents/pharmacology , Nitric Oxide Donors/toxicity , Retinal Ganglion Cells/drug effects , Animals , Cell Count , Cell Death/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Male , Nitroso Compounds/toxicity , Rats , Rats, Sprague-Dawley , Retinal Ganglion Cells/pathology
10.
Eur J Pharmacol ; 458(1-2): 81-9, 2003 Jan 01.
Article in English | MEDLINE | ID: mdl-12498910

ABSTRACT

Selegiline, a therapeutic agent of Parkinson's disease, and its metabolite, desmethylselegiline, were explored for their neuroprotective effects against N-methyl-D-aspartate (NMDA)-induced cell death in rat retina. Morphometric analysis of the retina revealed that an intravitreal injection of NMDA induced a significant decrease in cell density in the ganglion cell layer and in thickness of the inner plexiform layer, but not of other retinal layers such as the outer nuclear layer. Concurrent intravitreal injection of selegiline with NMDA did not show a significant protective effect, whereas co-injection of desmethylselegiline provided protection from NMDA-induced retinal damage. Parenteral administration (both single and consecutive dosing) of selegiline significantly prevented loss of ganglion cell layer cells. Counting of retinal ganglion cells by fluorescent tracer labeling confirmed that selegiline protected retinal ganglion cells from NMDA toxicity. The selegiline treatment did not produce a significant increase, though it tended to such as effect, in a brain-derived neurotrophic factor (BDNF) level in the retina, when compared with the NMDA-treated control group. These results indicate that parenteral treatment with selegiline rescues inner retinal cells from NMDA-induced neural damage, and that desmethylselegiline may contribute, in part, to the protective activities of selegiline. The neuroprotective effects exerted by selegiline may be attributed partially to a change in the retinal BDNF expression.


Subject(s)
Amphetamines/pharmacology , Neuroprotective Agents/pharmacology , Retina/drug effects , Selegiline/pharmacology , Animals , Brain-Derived Neurotrophic Factor/metabolism , Dizocilpine Maleate/pharmacology , Injections , Injections, Subcutaneous , Male , N-Methylaspartate/administration & dosage , Neurons/drug effects , Neurons/pathology , Rats , Rats, Sprague-Dawley , Retina/metabolism , Retina/pathology , Superior Colliculi/drug effects , Superior Colliculi/metabolism , Vitreous Body
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