Sunoh Kwon

Translating the N-methyl-d-aspartate receptor antagonist model of schizophrenia to treatments for cognitive impairment in schizophrenia

The N-methyl-D-aspartate receptor (NMDAR) antagonists, phencyclidine (PCP), dizocilpine (MK-801), or ketamine, given subchronically (sc) to rodents and primates, produce prolonged deficits in cognitive function, including novel object recognition (NOR), an analog of human declarative memory, one of the cognitive domains impaired in schizophrenia. Atypical antipsychotic drugs (AAPDs) have been reported to improve declarative memory in some patients with schizophrenia, as well as to ameliorate and prevent the NOR deficit in rodents following scNMDAR antagonist treatment. While the efficacy of AAPDs to improve cognitive impairment in schizophrenia (CIS) is limited, at best, and controversial, single doses of all currently available AAPDs so far tested transiently restore NOR in rodents following scNMDAR antagonist treatment. Typical antipsychotic drugs (APDs), e.g. haloperidol and perphenazine, are ineffective in this rodent model, and may be less effective as treatments of some domains of CIS. Serotonergic mechanisms, including, but not limited to serotonin (5-HT)2A and 5-HT7 antagonism, 5-HT(1A), and GABA(A) agonism, contribute to the efficacy of the AAPDs in the scNMDAR antagonist rodent models, which are relevant to the loss of GABA interneuron/hyperglutamate hypothesis of the etiology of CIS. The ability of sub-effective doses of the atypical APDs to ameliorate NOR in the scNMDAR-treated rodents can be restored by the addition of a sub-effective dose of the 5-HT(1A) partial agonist, tandospirone, or the 5-HT7 antagonist, SB269970. The mGluR2/3 agonist, LY379268, which itself is unable to restore NOR in the scNMDAR-treated rodents, can also restore NOR when given with lurasidone, an AAPD. Enhancing cortical and hippocampal dopamine and acetylcholine efflux, or both, may contribute to the restoration of NOR by the atypical APDs. Importantly, co-administration of lurasidone, tandospirone, or SB269970, with PCP, to rodents, at doses 5-10 fold greater than those acutely effective to restore NOR following scNMDAR treatment, prevents the effect of scPCP to produce an enduring deficit in NOR. This difference in dosage may be relevant to utilizing AAPDs to prevent the onset of CIS in individuals at high risk for developing schizophrenia. The scNMDAR paradigm may be useful for identifying possible means to treat and prevent CIS.

Ginsenoside Rg3 Alleviates Lipopolysaccharide-Induced Learning and Memory Impairments by Anti-Inflammatory Activity in Rats

The purpose of this study was to examine whether ginsenoside Rg3 (GRg3) could improve learning and memory impairments and inflammatory reactions induced by injecting lipopolysaccharide (LPS) into the brains of rats. The effects of GRg3 on proinflammatory mediators in the hippocampus and the underlying mechanisms of these effects were also investigated. Injection of LPS into the lateral ventricle caused chronic inflammation and produced deficits in learning in a memory-impairment animal model. Daily administration of GRg3 (10, 20, and 50 mg/kg, i.p.) for 21 consecutive days markedly improved the LPS-induced learning and memory disabilities demonstrated on the step-through passive avoidance test and Morris water maze test. GRg3 administration significantly decreased expression of pro-inflammatory mediators such as tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2 in the hippocampus, as assessed by reverse transcription-polymerase chain reaction analysis and immunohistochemistry. Together, these findings suggest that GRg3 significantly attenuated LPS-induced cognitive impairment by inhibiting the expression of pro-inflammatory mediators in the rat brain. These results suggest that GRg3 may be effective for preventing or slowing the development of neurological disorders, including Alzheimer’s disease, by improving cognitive and memory functions due to its anti-inflammatory activity in the brain.

Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism.

Atypical antipsychotic drugs (AAPDs) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APDs, a conclusion supported by differences in receptor affinities and neurotransmitter efflux in the cortex and the hippocampus. More potent serotonin (5‐HT)2A than dopamine (DA) D2 receptors antagonism, and direct or indirect 5‐HT1A agonism, characterize almost all AAPDs. Blonanserin, an AAPD, has slightly greater affinity for D2 than 5‐HT2A receptors. Using microdialysis and ultra performance liquid chromatography‐mass spectrometry/mass spectrometry, we compared the abilities of the typical APD, haloperidol, three AAPDs, blonanserin, lurasidone, and olanzapine, and a selective 5‐HT1A partial agonist, tandospirone, and all, except haloperidol, were found to ameliorate the cognitive deficits produced by the N‐methyl‐d‐aspartate antagonist, phencyclidine, altering the efflux of neurotransmitters and metabolites in the rat cortex and nucleus accumbens. Blonanserin, lurasidone, olanzapine, and tandospirone, but not haloperidol, increased the efflux of cortical DA and its metabolites, homovanillic acid and 3,4‐dihydroxyphenylacetic acid. Olanzapine and lurasidone increased the efflux of acetylcholine; lurasidone increased glutamate as well. None of the compounds significantly altered the efflux of 5‐HT or its metabolite, 5‐hydroxyindole acetic acid, or GABA, serine, and glycine. The ability to increase cortical DA efflux was the only shared effect of the compounds which ameliorates the deficit in cognition in rodents following phencyclidine.

Effect of wild ginseng on scopolamine‐induced acetylcholine depletion in the rat hippocampus

Objectives The ameliorating effects of wild ginseng on learning and memory deficits were investigated in rats.

Acupuncture Stimulation Alleviates Corticosterone-Induced Impairments of Spatial Memory and Cholinergic Neurons in Rats

The purpose of this study was to examine whether acupuncture improves spatial cognitive impairment induced by repeated corticosterone (CORT) administration in rats. The effect of acupuncture on the acetylcholinergic system was also investigated in the hippocampus. Male rats were subcutaneously injected with CORT (5 mg/kg) once daily for 21 days. Acupuncture stimulation was performed at the HT7 (Sinmun) acupoint for 5 min before CORT injection. HT7 acupoint is located at the end of transverse crease of ulnar wrist of forepaw. In CORT-treated rats, reduced spatial cognitive function was associated with significant increases in plasma CORT level (+36%) and hippocampal CORT level (+204%) compared with saline-treated rats. Acupuncture stimulation improved the escape latency for finding the platform in the Morris water maze. Consistently, the acupuncture significantly alleviated memory-associated decreases in cholinergic immunoreactivity and mRNA expression of BDNF and CREB in the hippocampus. These findings demonstrate that stimulation of HT7 acupoint produced significant neuroprotective activity against the neuronal impairment and memory dysfunction.

Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement.

Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS.

RP5063, an atypical antipsychotic drug with a unique pharmacologic profile, improves declarative memory and psychosis in mouse models of schizophrenia

&NA; Various types of atypical antipsychotic drugs (AAPDs) modestly improve the cognitive impairment associated with schizophrenia (CIAS). RP5063 is an AAPD with a diverse and unique pharmacology, including partial agonism at dopamine (DA) D2, D3, D4, serotonin (5‐HT)1A, and 5‐HT2A receptors (Rs), full agonism at &agr;4&bgr;2 nicotinic acetylcholine (ACh)R (nAChR), and antagonism at 5‐HT2B, 5‐HT6, and 5‐HT7Rs. Most atypical APDs are 5‐HT2A inverse agonists. The efficacy of RP5063 in mouse models of psychosis and episodic memory were studied. RP5063 blocked acute phencyclidine (PCP)‐as well as amphetamine‐induced hyperactivity, indicating antipsychotic activity. Acute administration of RP5063 significantly reversed subchronic (sc)PCP‐induced impairment in novel object recognition (NOR), a measure of episodic memory, but not reversal learning, a measure of executive function. Co‐administration of a sub‐effective dose (SED) of RP5063 with SEDs of a 5‐HT7R antagonist, a 5‐HT1BR antagonist, a 5‐HT2AR inverse agonist, or an &agr;4&bgr;2 nAChR agonist, restored the ability of RP5063 to ameliorate the NOR deficit in scPCP mice. Pre‐treatment with a 5‐HT1AR, a D4R, antagonist, but not an &agr;4&bgr;2 nAChR antagonist, blocked the ameliorating effect of RP5063. Further, co‐administration of scRP5063 prior to each dose of PCP prevented the effect of PCP to produce a deficit in NOR for one week. RP5063, given to scPCP‐treated mice for one week restored NOR for one week only. Acute administration of RP5063 significantly increased cortical DA efflux, which may be critical to some of its cognitive enhancing properties. These results indicate that RP5063, by itself, or as an adjunctive treatment has a multifaceted basis for improving some cognitive deficits associated with schizophrenia. HighlightsRP5063, an atypical antipsychotic drug (APD), blocked acute phencyclidine (PCP)‐ as well as amphetamine‐induced hyperactivity.Acute treatment with RP5063 reversed the subchronic (scPCP)‐induced novel object recognition (NOR) deficit in mice.Co‐administration of PCP and RP5063 for seven days, bid, delayed the onset of the deficit in NOR deficit for one week.ScRP5063 administered beginning one week after scPCP withdrawal reversed the NOR deficit for one week.RP5063 significantly increased cortical dopamine efflux in mice.

Proteomic Analysis of the Effect of Acupuncture on the Suppression of Kainic Acid-Induced Neuronal Destruction in Mouse Hippocampus

Kainic acid (KA) is a neurotoxin that induces epileptic seizures and excitotoxicity in the hippocampus. Acupuncture is frequently used as an alternative therapy for epilepsy, and it has been known to protect hippocampal neurons against KA toxicity. Using proteomic analysis, we investigated protein expression changes in the hippocampus following acupuncture stimulation at HT8. Eight-week-old male C57BL/6 mice (20–25 g) received acupuncture treatment at HT8 acupoint bilaterally once a day for 3 days and were then administered KA (30 mg/kg) intraperitoneally. Twenty-four hours after KA injection, neuronal survival and astrocyte activation in the hippocampus were measured, and protein expression in the hippocampus was identified by 2-dimensional electrophoresis. Acupuncture stimulation at HT8 suppressed KA-induced neuronal death and astrocyte activation in the hippocampus. We identified the changes in the expression of 11 proteins by KA or acupuncture stimulation at HT8 and found that acupuncture stimulation at HT8 normalized the expression of dihydropyrimidinase-related protein 2 and upregulated the expression of transcriptional activator protein pur-alpha, serine/threonine-protein phosphatase 5, and T-complex protein 1 subunit alpha, which are related to the survival of neurons. These results suggest that acupuncture stimulation at HT8 changes protein expression profiles in the hippocampus in favor of neuronal survival in KA-treated mice.

Acupuncture points for treating Parkinson’s disease based on animal studies

Parkinson’s disease (PD) is a well-known neurodegenerative disease caused by dopaminergic cell death in the nigrostriatal pathway. Recent studies have shown that acupuncture can be a potential therapy for the treatment of PD, but it is not clear which acupuncture points (acupoints) play major roles in reliving symptoms of PD. Yanglingquan (GB 34), Zusanli (ST 36), Fengfu (GV 16), Taichong (LR 3), Baihui (GV 20) and Dazhui (GV 14) acupoints have frequently been to investigate the effectiveness and action mechanism of acupuncture for treating PD, but it is not clear why they were selected. This review summarizes the current understanding of the acupoints for PD treatment based on Oriental medicine theories and on the accumulated findings from previous animal studies. The results of this study will be useful to development of a strategy for future research in this field.

Neurochemical arguments for the use of dopamine D4 receptor stimulation to improve cognitive impairment associated with schizophrenia

Background: Dopamine (DA) D4 receptors have been implicated in schizophrenia and the ability of some atypical antipsychotic drugs (APDs) to improve the cognitive impairment associated with schizophrenia (CIAS). Systemic administration of a D4 agonist, PD168077, at a sub‐effective dose, together with a sub‐effective dose of lurasidone, an atypical APD which is a weak D4 receptor antagonist, reversed the deficit in novel object recognition (NOR) in rats treated subchronically with phencyclidine (PCP), a rodent model of CIAS. Atypical APDs potentially stimulate D4Rs via their ability to enhance DA release in key brain areas related to cognition. However, some atypical APDs are relatively potent D4 antagonists at clinical dosages, including clozapine, and risperidone. The D4 antagonist, L745870, blocked the ability of clozapine, but not lurasidone, to reverse the NOR deficit in rats. Methods: The purpose of this study was to determine the effects of a selective D4 agonist and antagonist, alone, and as pretreatment with lurasidone, on neurotransmitter efflux in mouse medial prefrontal cortex (mPFC) and dorsal striatum (dSTR), using in vivo microdialysis. Results and discussion: PD168077 alone, and in combination with sub‐effective dose lurasidone, increased DA and acetylcholine (ACh) efflux in mPFC, but only DA efflux in dSTR. L745870 had no effect on neurotransmitter efflux on its own or on the ability of lurasidone to increase cortical or striatal neurotransmitter efflux. These results indicate D4 receptor agonism alone is sufficient to increase cortical DA and ACh efflux without interfering with the effects of lurasidone and possibly other atypical APDs on extracellular cortical DA and ACh levels. A D4 agonist may be useful for treating CIAS, especially as augmentation of those atypical APDs which are not potent D4 antagonists. HighlightsD4 receptor agonist increases basal cortical ACh and DA efflux.D4 receptor antagonist had no effect on basal neurotransmitter efflux.D4 receptor antagonist did not affect lurasidone‐induced neurotransmitter efflux.D4 receptor agonists can be used to improve cognitive impairment in schizophrenia.