Effect of D-pinitol on MK-801-induced schizophrenia-like behaviors in mice.

Schizophrenia is a chronic brain disorder characterized by positive symptoms (delusions or hallucinations), negative symptoms (impaired motivation or social withdrawal), and cognitive impairment. In the present study, we explored whether D-pinitol could ameliorate schizophrenia-like behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Acoustic startle response test was conducted to evaluate the effects of D-pinitol on sensorimotor gating function. Social interaction and novel object recognition tests were employed to measure the impact of D-pinitol on social behavior and cognitive function, respectively. Additionally, we examined whether D-pinitol affects motor coordination. Western blotting was conducted to investigate the mechanism of action of D-pinitol. Single administration of D-pinitol at 30, 100, or 300 mg/kg improved the sensorimotor gating deficit induced by MK801 in the acoustic startle response test. D-Pinitol also reversed social behavior deficits and cognitive impairments induced by MK-801 without causing any motor coordination deficits. Furthermore, D-pinitol reversed increased expression levels of pNF-kB induced by MK-801 treatment and consequently increased expression levels of TNF-α and IL-6 in the prefrontal cortex. These results suggest that D-pinitol could be a potential candidate for treating sensorimotor gating deficits and cognitive impairment observed in schizophrenia by down-regulating transcription factor NF-κB and pro-inflammatory cytokines in the prefrontal cortex.

Protective Effects of Shi-Zhen-An-Shen Decoction on the Cognitive Impairment in MK801-Induced Schizophrenia Model.

BACKGROUND: Cognitive dysfunction is a core feature of schizophrenia that strongly correlates to the patients' difficulties in independent living and occupational functioning. Synaptic dysfunction may result in cognitive and behavioral changes similar to what have been identified in schizophrenia. Shi-Zhen-An-Shen Decoction (SZASD) is the empirical formula of traditional Chinese medicine adopted in treating psychiatric symptoms, especially the cognitive impairment in schizophrenia patients, with proven efficacy in the long term of clinical practice in Beijing Anding Hospital, Capital Medical University. However, the mechanisms of SZASD on the cognitive improvement in schizophrenia is still unclear. Here, we aim to investigate the underlying mechanisms of the impact of SZASD on the cognitive impairment in MK801-induced schizophrenia-like rats. METHODS: Six rat groups (n = 12 per group) were subjected to different treatments for 14 days. All the six groups were injected intraperitoneally with a given volume of 0.9% saline and MK801 (0.2 mg/kg) for consecutive 14 days for modelling. And the rats in the SZASD-treated groups and the clozapine-treated group were given SZASD (low, middle, and high doses) or clozapine, respectively, by intragastric administration. Then, we performed behavioral tests after the treatments, and the rats were sacrificed on the 19th day for biological analysis. RESULTS: Behavioral tests indicated that SZASD mitigated the aberrant motor activity and improved schizophrenia-like rats' spatial reference memory and sensory gating ability. Furthermore, SZASD significantly increased the expressions of PSD95, BDNF, and synapsin I in the hippocampus of MK801-induced schizophrenia-like rats. CONCLUSIONS: Our findings suggest that SZASD may ameliorate cognitive impairment by restoring the levels of synaptic proteins in the hippocampus.

Corallodiscus flabellata B. L. Burtt extract and isonuomioside A ameliorate Aß25-35-induced brain injury by inhibiting apoptosis, oxidative stress, and autophagy via the NMDAR2B/CamK â ¡/PKG pathway.

BACKGROUND: Corallodiscus flabellata B. L. Burtt, a traditional Chinese folk medicine used for amnesia, can significantly improve brain injury; however, its active components and underlying mechanism of action remain unclear. OBJECTIVE: To examine the effects and underlying mechanism of action of Corallodiscus flabellata B. L. Burtt (SDC) extract and isolated isonuomioside A (isA) on Aß25-35-induced brain injury. METHODS: SDC extract (155 mg/kg, i.g.) or IsA (20 mg/kg, i.g.) was administered over a period of 4 weeks, following which brain injury was induced by Aß25-35 infusion (200 µM, 3 µl/20 g, i.c.v.). Network pharmacology research gathered existing data on the effects of SDC on Alzheimer's disease. Learning and memory ability, neuronal damage, and the levels of Aß1-42/Aß1-40, p-Tau, apoptosis, oxidative stress, autophagy, immune cells, NMDAR2B, p-CamK Ⅱ, and PKG were examined. Furthermore, the antagonistic effect of MK-801 (NMDA receptor blocker, 10 µM) in the presence of isA (10 µM) or SDC extract (20 µg/ml) was investigated in Aß25-35 (20 µM, 24 h)-induced PC-12 and N9 cells to evaluate whether the observed effects elicited by isA and SDC extract were mediated via the NMDAR2B/CamK Ⅱ/PKG pathway. RESULTS: IsA and SDC extract improved learning and memory ability, reduced neuronal damage, downregulated Aß1-42/Aß1-40, p-Tau, apoptosis, oxidative stress, and autophagy, transformed immune cells, and increased the expression levels of NMDAR2B, p-CamK Ⅱ, and PKG following Aß25-35 challenge. Moreover, MK-801 blocked the effects of isA and SDC extract on apoptosis, ROS levels, and autophagy in Aß25-35-induced N9 and PC-12 cells, indicating that isA and SDC extract likely exert neuroprotective effects via the NMDAR2B/CamK Ⅱ/PKG pathway. CONCLUSION: IsA and SDC extract ameliorate Aß25-35-induced brain injury by inhibiting apoptosis, oxidative stress, and autophagy, which likely occurs via the NMDAR2B/CamK Ⅱ/PKG pathway. These findings may help to elucidate new therapeutic targets and facilitate the development of drugs for the clinical treatment of AD.

Preclinical characterization of AMPA receptor potentiator TAK-137 as a therapeutic drug for schizophrenia.

The downregulation of the glutamate system may be involved in positive, negative, and cognitive symptoms of schizophrenia. Through enhanced glutamate signaling, the activation of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor, an ionotropic glutamate receptor, could be a new therapeutic strategy for schizophrenia. TAK-137 is a novel AMPA receptor potentiator with minimal agonistic activity; in this study, we used rodents and nonhuman primates to assess its potential as a drug for schizophrenia. At 10 mg kg-1 p.o., TAK-137 partially inhibited methamphetamine-induced hyperlocomotion in rats, and at 3, 10, and 30 mg kg-1 p.o., TAK-137 partially inhibited MK-801-induced hyperlocomotion in mice, suggesting weak effects on the positive symptoms of schizophrenia. At 0.1 and 0.3 mg kg-1 p.o., TAK-137 significantly ameliorated MK-801-induced deficits in the social interaction of rats, demonstrating potential improvement of impaired social functioning, which is a negative symptom of schizophrenia. The effects of TAK-137 were evaluated on multiple cognitive domains-attention, working memory, and cognitive flexibility. TAK-137 enhanced attention in the five-choice serial reaction time task in rats at 0.2 mg kg-1 p.o., and improved working memory both in rats and monkeys: 0.2 and 0.6 mg kg-1 p.o. ameliorated MK-801-induced deficits in the radial arm maze test in rats, and 0.1 mg kg-1 p.o. improved the performance of ketamine-treated monkeys in the delayed matching-to-sample task. At 0.1 and 1 mg kg-1 p.o., TAK-137 improved the cognitive flexibility of subchronic phencyclidine-treated rats in the reversal learning test. Thus, TAK-137-type AMPA receptor potentiators with low intrinsic activity may offer new therapies for schizophrenia.

Investigation of the synergistic effects of haloperidol combined with Calculus Bovis Sativus in treating MK-801-induced schizophrenia in rats.

Clinical studies that focused on treating schizophrenia showed that Calculus Bovis Sativus (CBS), a substitute of Calculus Bovis, when used in combination with haloperidol could significantly lower the dosage of haloperidol compared with treatment with haloperidol alone, whereas efficacy was maintained. The aim of this study was to investigate the synergetic anti-schizophrenia effects in rats using CBS in combination with haloperidol. An open field test was conducted to verify the pharmacodynamic effects of a combination treatment of CBS and haloperidol on MK-801-induced schizophrenic rats. Rat plasma concentrations of intragastric haloperidol and intravenous haloperidol were determined after oral administration of a single dose or 1-week of pretreatment with CBS (50 mg/kg). The pharmacodynamic data showed a significant decrease in locomotor activity and an increase in the percentage of the central distance when haloperidol was concomitantly administered with CBS compared with haloperidol administration alone. The AUC0-∞ and Cmax of haloperidol in the orally coadministered groups were significantly higher compared with the oral treatment with haloperidol alone. In conclusion, oral coadministration of CBS with haloperidol resulted in a synergistic effect in rats. The enhanced oral bioavailability of haloperidol when combined with CBS might be attributed to the interaction between them.

Permeation of Polymethoxyflavones into the Mouse Brain and Their Effect on MK-801-Induced Locomotive Hyperactivity.

Accumulating data have indicated that citrus polymethoxyflavones (PMFs) have the ability to affect brain function. In the present study, we showed that 3,5,6,7,8,3',4'-heptamethoxy- flavone (HMF) given intraperitoneally to mice was immediately detected in the brain and that the permeability of the brain tissues to it was significantly higher than that of other citrus PMFs (nobiletin, tangeretin, and natsudaidain). The permeation of these PMFs into the brain well correlated with their abilities to suppress MK-801-induced locomotive hyperactivity, suggesting that HMF had the ability to act directly in the brain. We also obtained data suggesting that the suppressive effect of HMF on MK-801-induced locomotive hyperactivity was mediated by phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the hippocampus.

Swertisin ameliorates pre-pulse inhibition deficits and cognitive impairment induced by MK-801 in mice.

Swertisin, a plant-derived C-glucosylflavone, is known to have antidiabetic, anti-inflammatory and antioxidant effects. In the present study, we investigated in mice the effects of swertisin on glutamatergic dysfunction induced by dizocilpine (MK-801), a non-competitive N-methyl-D-aspartate receptor antagonist. In the Acoustic Startle Response test, their MK-801-induced (given 0.2 mg/kg i.p.) pre-pulse inhibition deficit was significantly attenuated by the administration of swertisin (30 mg/kg p.o.). In the Novel Object Recognition Test, the recognition memory impairments that were induced by MK-801 (0.2 mg/kg, given i.p.) were also reversed by administration of swertisin (30 mg/kg p.o.). In addition, swertisin normalized the MK-801-induced elevation of phosphorylation levels of Akt and GSK-3ß signaling molecules in the prefrontal cortex. These results indicated that swertisin may be useful in managing the symptoms of schizophrenia, including sensorimotor gating disruption and cognitive impairment, and that these behavioral outcomes may be related to Akt-GSK-3ß signaling in the prefrontal cortex.

Synthesis and biological evaluation of novel flavanone derivatives as potential antipsychotic agents.

In this study, a series of novel flavanone derivatives were designed and synthesized, and the antipsychotic activities of the target compounds were evaluated in vitro and in vivo. The results showed that synthesized compounds 7a-7g decreased the activity of dopamine D2 receptors in HEK293 cells co-transfected with D2 receptor/G protein α16a, with IC50 values of 0.051-0.35 µm. Compounds 7a-7g inhibited the over-production of nitric oxide stimulated by lipopolysaccharide/interferon-γ in BV-2 microglial cells. In mice, intragastric administration of 7d, 7e, and 7g reversed the increase in locomotor activity induced by MK-801 (an antagonist of NMDA receptors) and decreased the hyperactivity of climbing behavior induced by apomorphine (a dopamine receptor agonist). These results suggest that some of the novel flavanone derivatives have potential antipsychotic effects and may be useful in the treatment of schizophrenia.

The effects of selective antagonists of serotonin 5-HT7 and 5-HT1A receptors on MK-801-induced impairment of learning and memory in the passive avoidance and Morris water maze tests in rats: mechanistic implications for the beneficial effects of the novel atypical antipsychotic lurasidone.

We have previously reported that lurasidone, a novel atypical antipsychotic with potent serotonin 5-HT(7) antagonist and 5-HT(1A) partial agonist activities, is superior to other antipsychotics in improving the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801-induced learning and memory impairment in the passive avoidance (PA) and Morris water maze (MWM) tests in rats. In this study, we investigated the effects of selective antagonists of 5-HT(7) and 5-HT(1A) receptors (SB-656104-A and WAY-100635, respectively) on MK-801-induced learning and memory impairment in the same tests. In the PA test, either pre-training (3 and 10mg/kg, p.o.) or post-training (0.3mg/kg, i.v.) administration of lurasidone significantly reversed the test response impaired by MK-801, consistent with our previous reports. Pre-training administration of either SB-656104-A (10 and 30 mg/kg, i.p.) or WAY-100635 (1mg/kg, s.c.) also significantly reversed MK-801-induced memory impairment. Furthermore, post-training administration of either SB-656104-A (0.3mg/kg, i.v.) or WAY-100635 (0.01 mg/kg, i.v.) counteracted the effect of MK-801, which suggested that both 5-HT receptor subtype-selective antagonists could restore the memory consolidation process. In the MWM test, SB-656104-A (3mg/kg, i.p.) reversed learning impairment induced by MK-801. On the other hand, WAY-100635 (0.3 and 1mg/kg, i.p.) did not have any effect on the MK-801-induced learning impairment. Taken together, our results showed that 5-HT(7) and 5-HT(1A) receptor antagonists mimic the effect of lurasidone in whole or in part, respectively, to reverse MK-801-induced learning and memory impairment, which warrants further investigation of the interaction of lurasidone with these serotonin receptors as a possible mechanism underlying its procognitive effects in these animal models.

The N-Methyl-D-aspartate receptor antagonist dizocilpine inhibits associative antinociceptive tolerance to morphine in mice: relation with memory.

I and coauthor previously reported the memory facilitation effect of morphine. The main purpose of this study was to evaluate the involvement of the N-methyl-D-aspartate (NMDA) receptor in associative tolerance to morphine by a contextual procedure. Antinociceptive response latency was measured by the tail-pinch method during repeated morphine (5 mg/kg, s.c.) injection for four consecutive days with pretreatment by dizocilpine (0.01, 0.05, 0.1 mg/kg, i.p.) at 30 min prior to morphine injection in the training phase and before and after morphine injection in the test phase. The nociceptive response latency was shortened by the single administration of dizocilpine (0.05 to 0.25 mg/kg, i.p.). Pretreatment by dizocilpine at 0.05 or 0.1 mg/kg weakened the antinociception to morphine on Day 1, but decreased the tolerance throughout the training phase. In the test phase, the animals were allocated into the same and different contexts. In the test phase, hyperalgesia before morphine injection in the same context and antinociception after morphine injection in the different context were evident in the saline-pretreated group in the training phase, but they were not observed in those contexts in the dizocilpine-pretreated groups. These results suggest that memory dysfunction with dizocilpine inhibits the recovery of associative tolerance to morphine by contextual change.

Atypical antipsychotic profile of flunarizine in animal models.

RATIONALE: Flunarizine is known as a calcium channel blocker commonly used in many countries to treat migraine and vertigo. Parkinsonism has been described as one of its side-effects in the elderly, which is in agreement with its recently characterized moderate D2 receptor antagonism. OBJECTIVES: To perform a pre-clinical evaluation of flunarizine as a potential antipsychotic. METHODS: We evaluated the action of orally administered flunarizine in mice against hyperlocomotion induced by amphetamine and dizocilpine (MK-801) as pharmacological models of schizophrenia, induction of catalepsy as a measure for extrapyramidal symptoms and impairment induced by dizocilpine on the delayed alternation task for working memory. RESULTS: Flunarizine robustly inhibited hyperlocomotion induced by both amphetamine and dizocilpine at doses that do not reduce spontaneous locomotion (3-30 mg/kg). Mild catalepsy was observed at 30 mg/kg, being more pronounced at 50 mg/kg and 100 mg/kg. Flunarizine (30 mg/kg) improved dizocilpine-induced impairment on the delayed alternation test. CONCLUSIONS: These results suggest a profile comparable to atypical antipsychotics. The low cost, good tolerability and long half-life (over 2 weeks) of flunarizine are possible advantages for its use as an atypical antipsychotic. These results warrant clinical trials with flunarizine for the treatment of schizophrenia.

A competitive antagonist of NMDA receptors CGP 40116 attenuates experimental symptoms of schizophrenia evoked by MK-801.

In the present study, the interaction between a noncompetitive [(+)-MK-801] and a competitive (CGP 40116) NMDA receptor antagonists was tested in two different behavioral paradigms: locomotor activity test and prepulse inhibition of the acoustic startle reflex. Additionally, their effects on working memory and selective attention were evaluated in the delayed alternation task. All above paradigms served to model the symptoms of schizophrenia. It was found that locomotor stimulatory effect of (+)-MK-801 (0.4 mg/kg) was antagonized by prior administration of CGP 40116 (5 mg/kg). Lower doses of CGP 40116 (1.25 and 2.5 mg/kg) were ineffective. CGP 40116 given alone did not influence locomotor activity in rats. It was also shown that CGP 40116 antagonized the disruption of the process of sensorimotor gating evoked by (+)-MK-801. On the contrary, both CGP 40116 and (+)-MK-801 increased a number of errors in the delayed alternation test revealing detrimental effect of CGP 40116 on spatial working memory and selective attention even at a lower dose than that required to antagonize the effects of (+)-MK-801. The presented results indicate that noncompetitive and competitive NMDA receptor antagonists, when used at relatively low doses, may produce qualitatively different behavioral effects, as evidenced by the experiments with locomotor activity and prepulse inhibition. Moreover, the competitive NMDA receptor antagonists may even inhibit some psychotomimetic effects related to the noncompetitive blockade of this receptor. However, therapeutic potential of CGP 40116, a competitive NMDA receptor antagonist, should be considered with caution since in the range of doses effective against the psychotomimetic effects of (+)-MK-801, it impairs rats' performance in the delayed alternation paradigm, i.e. it worsens efficacy of working memory.

Validation of corneally kindled mice: a sensitive screening model for partial epilepsy in man.

Epileptogenesis induced by electrical kindling of rats appears to be superior to the acute maximal electroshock seizure (MES) test in normal animals in predicting the efficacy and adverse effect potential of drugs in patients with partial epilepsy. Unfortunately, inclusion of such kindling models in primary screening is hampered by the laborious and expensive procedure of stimulation and recording with implanted brain electrodes. Furthermore the size of the rats excludes their use in initial testing where compound availability is often limited for the 'first batch synthesis'. The present study demonstrates that chronic electrical stimulation with corneal electrodes in mice can rapidly yield large numbers of kindled animals with a seizure phenomenology reflecting partial seizures in man. A pharmacological characterisation showed that corneally kindled mice can be used repeatedly for several drug experiments with reproducible results. The seizure protection and adverse effect potential obtained with proven antiepileptic drugs were similar to the effects observed in amygdala kindled rats and their corresponding clinical profile in partial epilepsy. Protection was obtained with vigabatrin and levetiracetam in this new model despite their lack of anticonvulsant activity in the acute MES test. Furthermore, in agreement with clinical findings with NMDA antagonists, MK-801 revealed more severe adverse effects in corneally kindled mice than in normal animals. These results suggest that corneal kindling of mice represents a sensitive and valid screening model for the identification of new therapies for partial epilepsy in man.