1-(3-4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine-dihydrochloride and Cognition-Disorders

Approximately 30-40% of patients with Parkinson's disease (PD) exhibit cognitive impairments. However, there are currently no clinically effective drugs for the treatment of cognitive impairment in patients with PD. Previous studies have suggested that mitochondrial dysfunction such as decreased adenosine triphosphate (ATP) production triggers dopaminergic neurodegeneration in patients with PD and that mitochondria represent a potential target for the development of novel treatments for preventing PD. Therefore, in the present study, we investigated the cognition-enhancing effects of ethyl pyruvate (EP) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride (SA4503) in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. PD model mice were generated via treatment with MPTP (25 mg/kg, i.p.) once a day for 5 consecutive days. Twenty-four hours after the final injection of MPTP, mice were intraperitoneally injected with EP (25, 50, 100 mg/kg) or SA4503 (1 mg/kg) once a day for 4 weeks. Chronic administration of EP (100 mg/kg i.p.) or SA4503 (1 mg/kg, i.p.) improved both motor deficits and cognitive impairments in MPTP-treated mice. Furthermore, treatment with EP or SA4503 attenuated decreases in the levels of ATP and tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc)/ventral tegmental area (VTA), striatum, and hippocampal CA1 region. Administration of EP or SA4503 protected the dopaminergic neurons from MPTP-induce toxicity and restored the dopamine levels in the striatum. Elevated 4-hydroxy-2-nonenal- (4-HNE-) and nitrotyrosine-reactive protein levels induced by MPTP-treatment were suppressed by EP or SA4503 treatment in the SNpc-VTA, striatum, and hippocampal CA1 region. These observations suggest that EP and SA4503 attenuate cognitive impairments and motor dysfunction in mice with MPTP-induced PD.

Topics: Adenosine Triphosphate; Animals; Avoidance Learning; CA1 Region, Hippocampal; Cognition Disorders; Dopamine; Dopaminergic Neurons; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinsonian Disorders; Pars Compacta; Piperazines; Pyruvates; Receptors, sigma; Rotarod Performance Test; Spatial Memory; Substantia Nigra; Ventral Tegmental Area

This study was undertaken to examine the effects of the selective serotonin reuptake inhibitors fluvoxamine and paroxetine on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg/day, 10 days) significantly decreased the exploratory preference in the retention test session, but not in the training test session. PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of fluvoxamine (20 mg/kg/day), but not paroxetine (10 mg/kg/day). Furthermore, the effect of fluvoxamine on PCP-induced cognitive deficits was antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1 mg/kg/day). Moreover, PCP-induced cognitive deficits were also significantly improved by subsequent subchronic (2-week) administration of the selective sigma-1 receptor agonist SA4503 (1 mg/kg/day) or neurosteroid dehydroepiandrosterone 3-sulfate (DHEA-S; 25 mg/kg/day). The effects of SA4503 or DHEA-S were also antagonized by co-administration of NE-100 (1 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of these drugs. In contrast, acute single administration of these drugs (fluvoxamine, paroxetine, SA4503) alone or combination with NE-100 did not alter PCP-induced cognitive deficits. The present study suggests that agonistic activity of fluvoxamine at sigma-1 receptors plays a role in the active mechanisms of fluvoxamine on PCP-induced cognitive deficits in mice. Therefore, sigma-1 receptor agonists such as fluvoxamine would be potential therapeutic drugs for the treatment of the cognitive deficits of schizophrenia.

Topics: Analysis of Variance; Animals; Anisoles; Antipsychotic Agents; Behavior, Animal; Choice Behavior; Cognition Disorders; Dehydroepiandrosterone Sulfate; Drug Administration Schedule; Drug Interactions; Exploratory Behavior; Fluvoxamine; Mice; Mice, Inbred ICR; Motor Activity; Nootropic Agents; Phencyclidine; Piperazines; Propylamines; Receptors, sigma; Retention, Psychology; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor