Hiroko Tsunekawa

Effects of a Novel Cognitive Enhancer, Spiro[imidazo-[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), on Learning Impairments Induced by Amyloid-β1–40 in the Rat

We have previously shown that intracerebroventricular (i.c.v.) infusion of amyloid-β (Aβ)1–40 produces oxidative stress and cholinergic dysfunction, as well as learning and memory deficits, in rats. In the present study, effects of a newly synthesized azaindolizinone derivative, spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), were assessed in rats with learning deficits induced by Aβ1–40 or scopolamine. The i.c.v. infusion of Aβ1–40 caused impairments in spontaneous alternation behavior in a Y-maze task, spatial reference and short-term memory in a water-maze task, and retention of passive-avoidance learning. Aβ1–40-infused rats also showed reduction in choline acetyltransferase (ChAT) activity in the medial septum and hippocampus, but not in the basal forebrain and cortex, and a decrease in glutathione S-transferase (GST)-like immunoreactivity in the cortex. Nicotine-stimulated acetylcholine (ACh) release in Aβ1–40-infused rats was lower than that in vehicle-infused rats. Oral administration of ZSET1446 at the dose range of 0.01 to 1 mg/kg ameliorated Aβ1–40-induced learning impairment in Y-maze, water-maze, and passive-avoidance tasks. ZSET1446 reversed the decrease of ChAT activity in the medial septum and hippocampus, GST-like immunoreactivity in the cortex, and nicotine-stimulated ACh release of Aβ1–40-treated rats to the levels of vehicle-infused control rats. Furthermore, 0.001 to 0.1 mg/kg ZSET1446 showed ameliorative effects on learning impairments caused by scopolamine in a passive-avoidance task. These results suggest that ZSET1446 may be a potential candidate for development as a therapeutic agent to manage cognitive impairment associated with conditions such as Alzheimers disease.

Behavioural and neurochemical features of olfactory bulbectomized rats resembling depression with comorbid anxiety.

In order to probe the nature and validity of olfactory bulbectomized (OB) rats as a model of depression, we reevaluated their behavioural and neurochemical deficits in relation to the symptoms and neurochemical abnormalities of depression using our protocols, which distinguish anhedonia-resembling behaviour in sexual behavioural test, the hippocampus (Hip)-dependent long-term memory and anxiety-resembling behaviour specially. Besides exploratory hyperactivity in response to a novel environmental stress resembling the psychomotor agitation, OB rats showed a decrease of libido, and a deficit of long-term explicit memory, resembling loss of interest and cognitive deficits in depressive patients, respectively. OB rats also exhibited the anxiety symptom-resembling behaviour in social interaction and plus-maze tests. In the OB rats, we found degenerated neurons in the piriform cortex, decreased protein expression of NMDA receptor subunit 1 (NR1), but not NR2A or NR2B, in the prefrontal cortex (PFC), Hip and amygdala (Amg), and decreased phosphorylation of cAMP-response element-binding protein (CREB) in the PFC and Hip, but not Amg. The behavioural and neurochemical abnormalities in OB rats, except for the performance in the plus-maze task and neuronal degeneration, were significantly attenuated by repeated treatment with desipramine (10 mg/kg), a typical antidepressant. The present study indicated that OB rats may be a model of depression with comorbid anxiety, characterized by agitation, sexual and cognitive dysfunction, neuronal degeneration, decreased protein expression of NR1, and decreased phosphorylation of CREB.

Synergistic effects of selegiline and donepezil on cognitive impairment induced by amyloid beta (25–35)

Selegiline, an irreversible inhibitor of monoamine oxidase B used in the treatment of Parkinsons disease, has been demonstrated to have a potential cognition-improving effect in patients with Alzheimers disease (AD) undergoing treatment with an acetylcholinesterase inhibitor donepezil. To confirm such clinical events, we investigated whether co-administration of donepezil with selegiline had a synergistic cognition-improving effect in an animal model of AD. Intracerebroventricular injection of amyloid beta protein fragment 25-35 [Abeta(25-35)] induced impairment of learning and memory in a Y-maze, novel object recognition and contextual fear conditioning tests. Either donepezil or selegiline alone improved the cognitive impairments in the Y-maze and conditioned fear learning tasks in Abeta(25-35)-injected mice, whereas donepezil, but not selegiline, failed to improve the impairment in a novel object recognition task. Co-administration of donepezil with selegiline, at doses that do not exert efficacy individually, significantly improved the deficits in all three tests, indicating a synergistic cognition-improving effect. These alleviating effects were antagonized by pretreatment with a muscarinic receptor antagonist scopolamine and a dopamine receptor antagonist haloperidol. These results suggest that selegiline potentiates the effect of donepezil on the cognitive impairment, and that the synergistic effect may be mediated through both the cholinergic and dopaminergic systems.

Matrix Metalloprotease-9 Inhibition Improves Amyloid β-Mediated Cognitive Impairment and Neurotoxicity in Mice

In Alzheimers disease (AD), the expression of matrix metalloproteases (MMPs), which are capable of degrading extracellular matrix proteins, is increased in the brain. Previous studies with cultured glial cells have demonstrated that amyloid β (Aβ) protein can induce the expression of MMPs, which could be involved in the degradation of Aβ. In the present study, we investigated the role of MMP-2 and MMP-9 in cognitive impairment induced by the injection of Aβ in mice. The intracerebroventricular injection of Aβ25-35, Aβ1-40, and Aβ1-42, but not Aβ40-1, transiently increased MMP-9, but not MMP-2, activity and protein expression in the hippocampus. Immunohistochemistry revealed the expression of MMP-9 to be increased in both neurons and glial cells in the hippocampus after Aβ treatment. The Aβ-induced cognitive impairment in vivo as well as neurotoxicity in vitro was significantly alleviated in MMP-9 homozygous knockout mice and by treatment with MMP inhibitors. These results suggest the increase in MMP-9 expression in the hippocampus to be involved in the development of cognitive impairment induced by Aβ1-40. Thus, specific inhibitors of MMP-9 may have therapeutic potential for the treatment of AD. Our findings suggest that, as opposed to expectations based on previous findings, MMP-9 plays a causal role in Aβ-induced cognitive impairment and neurotoxicity.

Myocardial nerve fibers are preserved in MPTP-treated mice, despite cardiac sympathetic dysfunction

Recently, we reported a profound depletion of cardiac sympathetic nerve fibers in Parkinsons disease (PD). This cardiac sympathetic denervation is a characteristic hallmark of PD. Cardiac sympathetic dysfunction was also observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP)-treated mice, a model of PD. Although binding assay showed a decreased density of norepinephrine transporter (NET) in the hearts of the mice, their histopathological alterations have not been demonstrated. In this study, we investigated hearts of MPTP-treated mice with immunohistochemical method and Western blot analyses. MPTP-treated mice showed significant decreases in the contents of cardiac noradrenaline and dopamine, suggesting the sympathetic dysfunction. Synaptophysin-, tyrosine hydroxylase- or NET-immunoreactive nerve fibers were abundant in the hearts of control mice and MPTP-treated mice, without apparent differences between the two groups. Western blot analyses also showed no difference in the amounts of these proteins. Myocardial nerve fibers were well preserved in MPTP-treated mice, despite apparent cardiac sympathetic dysfunction.

Role of N-Methyl-D-aspartate Receptors in Antidepressant-Like Effects of σ1 Receptor Agonist 1-(3,4-Dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine Dihydrochloride (SA-4503) in Olfactory Bulbectomized Rats

In the present study, we aimed to investigate the role of N-methyl-d-aspartate (NMDA) receptors in the antidepressant-like effects of a σ1 receptor agonist, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA-4503), in the olfactory bulbectomized (OB) rat model of depression. A symptomatology-based behavioral investigation was made by reconstructing in OB rats the symptoms of depression, such as psychomotor agitation, loss of interest, and cognitive dysfunction, using a typical antidepressant, desipramine, as a positive control. Repeated treatment with SA-4503 ameliorated the behavioral deficits in OB rats resembling depression symptoms in the open-field test, sexual behavior test, and cued and contextual fear-conditioning test. SA-4503 displayed advantages over desipramine in the sexual behavior test. SA-4503 also reversed the decrease in the protein expression of NMDA receptor subunit (NR)1, but not NR2A or NR2B, in the prefrontal cortex, hippocampus, and amygdala of OB rats. The behavioral and neurochemical effects of SA-4503 were blocked by combined treatment with a specific σ1 receptor antagonist, N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride (NE-100). Furthermore, the effects of SA-4503 on the performance of OB rats in the behavioral tests were abrogated by acute treatment with an NMDA receptor antagonist, (–)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801). The present study indicated for the first time that the σ1 receptor agonist SA-4503 may have effects on depressive symptoms such as agitation, loss of interest, and impaired cognition, which are mediated by NMDA receptors.

Effects of (R)-(-)-1-(benzofuran-2-yl)-2-propylaminopentane hydrochloride [(-)-BPAP] in animal models of mood disorders

(R)-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane hydrochloride [(-)-BPAP] is a highly potent enhancer of impulse propagation-mediated monoamine release and an inhibitor of monoamine uptake. We evaluated the efficacy of (-)-BPAP as a drug for mood disorders by using two animal models. (1) Acute, but not chronic, administration of (-)-BPAP and imipramine significantly attenuated immobility in mice induced by forced swimming. Chronic, but not acute, administration of (-)-BPAP ameliorated the impairment of social interaction (SI) behavior following forced swimming, without affecting locomotor activity. The ameliorating effect of (-)-BPAP on the impairment of SI behavior was suppressed by dopamine receptor antagonists, which suggests that the effect was mediated through the activation of the dopaminergic system. Chronic administration of imipramine tended to attenuate the impairment of SI behavior in stressed mice, but not significantly. (2) In the olfactory bulbectomized (OB) rat, chronic (-)-BPAP treatment significantly ameliorated the impairment of SI behavior, prepulse inhibition, and tone-cue fear learning, without affecting locomotor activity in an open field and circadian activity pattern. Furthermore, (-)-BPAP tended to improve sexual dysfunction in OB rats, but imipramine had no such effect. These findings suggest that (-)-BPAP may be clinically effective in treating mood disorders, including comorbid anxiety and depression that are poorly responsive to imipramine.

Selegiline increases on time without exacerbation of dyskinesia in 6-hydroxydopamine-lesioned rats displaying l-Dopa-induced wearing-off and abnormal involuntary movements

HighlightsSelegiline extends l‐Dopa‐induced shortened on time in hemi‐parkinsonian rats.Selegiline does not exacerbate l‐Dopa‐induced dyskinesia in hemi‐parkinsonian rats.Selegiline does not alter PDy and Arc mRNA expression in the lesioned striatum. 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.

Selegiline ameliorates depression-like behaviors in rodents and modulates hippocampal dopaminergic transmission and synaptic plasticity

HighlightsRepeated selegiline injection reduces immobility time in rodent depression tests.Antidepressant‐like action of selegiline is independent of MAO‐A inhibition.Selegiline increases DA content and prevents LTP impairment in the hippocampus. 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.