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1.
Nature ; 629(8014): 1133-1141, 2024 May.
Article in English | MEDLINE | ID: mdl-38750368

ABSTRACT

The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.


Subject(s)
Dizocilpine Maleate , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Obesity , Receptors, N-Methyl-D-Aspartate , Animals , Humans , Male , Mice , Rats , Brain Stem/metabolism , Brain Stem/drug effects , Disease Models, Animal , Dizocilpine Maleate/adverse effects , Dizocilpine Maleate/pharmacology , Dizocilpine Maleate/therapeutic use , Dyslipidemias/drug therapy , Dyslipidemias/metabolism , Glucagon-Like Peptide 1/metabolism , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/metabolism , Hyperglycemia/drug therapy , Hyperglycemia/metabolism , Hypothalamus/drug effects , Hypothalamus/metabolism , Mice, Inbred C57BL , Neuronal Plasticity/drug effects , Obesity/drug therapy , Obesity/metabolism , Rats, Sprague-Dawley , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
2.
Behav Brain Res ; 461: 114838, 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38157989

ABSTRACT

Schizophrenia has been linked to cognitive impairment and white matter damage in a growing number of studies this year. In this study, we used the MK-801-induced schizophrenia-like mice model to investigate the effects of quetiapine on behavioral changes and myelin loss in the model mice. The subjects selected for this study were C57B6/J male mice, MK-801 (1 mg/kg/d intraperitoneal injection) modeling for 1 week and quetiapine (10 mg/kg/d intraperitoneal injection) treatment for 2 weeks. Behavioral tests were then performed using the three-chamber paradigm test and the Y maze test. Moreover, western blot, immunohistochemistry, and immunofluorescence were conducted to investigate the changes in oligodendrocyte spectrum markers. In addition, we performed some mechanism-related proteins by western blot. Quetiapine ameliorated cognitive impairment and cerebral white matter damage in MK-801 model mice, and the mechanism may be related to the PI3K/AKT pathways. The present study suggests that quetiapine has a possible mechanism for treating cognitive impairment and white matter damage caused by schizophrenia.


Subject(s)
Cognitive Dysfunction , Schizophrenia , White Matter , Humans , Male , Mice , Animals , Quetiapine Fumarate/pharmacology , Schizophrenia/chemically induced , Schizophrenia/drug therapy , Schizophrenia/metabolism , Dizocilpine Maleate/adverse effects , White Matter/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Cognitive Dysfunction/drug therapy
3.
Phytother Res ; 37(12): 5904-5915, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37654104

ABSTRACT

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.


Subject(s)
Cognitive Dysfunction , Schizophrenia , Mice , Animals , Dizocilpine Maleate/adverse effects , Reflex, Startle/physiology , Schizophrenia/chemically induced , Schizophrenia/drug therapy , Schizophrenia/metabolism , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy
4.
Int J Mol Sci ; 23(24)2022 Dec 14.
Article in English | MEDLINE | ID: mdl-36555568

ABSTRACT

Schizophrenia is a chronic mental illness, which remains difficult to treat. A high resistance to the available therapies, their insufficient efficacy, and numerous side effects are the reasons why there is an urgent need to develop new antipsychotics. This study aimed to assess the antipsychotic-like effects of JJGW08, a novel arylpiperazine alkyl derivative of salicylamide, in rodents. First, considering the JJGW08 receptor profile, we investigated the compound's intrinsic activity towards dopamine D2 and serotonin 5-HT1A, 5-HT2A, and 5-HT7 receptors using functional assays. Next, we assessed the effect of JJGW08 on MK-801- and amphetamine-induced hyperlocomotion, its risk of inducing catalepsy and impairing motor coordination, as well as the anxiolytic-like effects in the four-plate and marble burying tests in mice. Finally, we investigated the antipsychotic-like properties of JJGW08 in rats using MK-801-induced hyperlocomotion and prepulse inhibition tests. We found that JJGW08 showed antagonistic properties at dopamine D2 and serotonin 5-HT1A, 5-HT2A, and 5-HT7 receptors. However, the effect on the 5-HT2A and 5-HT7 receptors was very weak. Moreover, the tested compound showed an antipsychotic-like effect in MK-801- and amphetamine-induced hyperlocomotion but not in a prepulse inhibition test in rats. Notably, JJGW08 demonstrated anxiolytic-like properties in both behavioral tests. Importantly, the compound did not induce catalepsy or motor coordination impairment in mice at antipsychotic-like doses. Our study suggests it is worth searching for new potential antipsychotics among arylpiperazine alkyl derivatives of salicylamide.


Subject(s)
Anti-Anxiety Agents , Antipsychotic Agents , Rats , Mice , Animals , Antipsychotic Agents/adverse effects , Serotonin/adverse effects , Anti-Anxiety Agents/pharmacology , Dopamine/adverse effects , Rodentia , Dizocilpine Maleate/adverse effects , Catalepsy/chemically induced , Catalepsy/drug therapy , Amphetamine/pharmacology
5.
J Integr Neurosci ; 21(6): 164, 2022 Sep 27.
Article in English | MEDLINE | ID: mdl-36424738

ABSTRACT

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.


Subject(s)
Clozapine , Cognitive Dysfunction , Schizophrenia , Rats , Animals , Dizocilpine Maleate/adverse effects , Schizophrenia/chemically induced , Schizophrenia/complications , Schizophrenia/drug therapy , Clozapine/adverse effects , Disease Models, Animal , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy
6.
Phytomedicine ; 101: 154114, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35489325

ABSTRACT

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.


Subject(s)
Alzheimer Disease , Brain Injuries , Neuroprotective Agents , Alzheimer Disease/chemically induced , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/toxicity , Apoptosis , Autophagy , Dizocilpine Maleate/adverse effects , Humans , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Oxidative Stress , Peptide Fragments/metabolism , Plant Extracts/therapeutic use , Receptors, N-Methyl-D-Aspartate/metabolism
7.
Curr Neuropharmacol ; 20(12): 2369-2380, 2022 Nov 15.
Article in English | MEDLINE | ID: mdl-35272593

ABSTRACT

BACKGROUND: GABAergic deficits have been considered to be associated with the pathophysiology of schizophrenia, and hence, GABA receptors subtype A (GABAARs) modulators, such as commonly used volatile anesthetic sevoflurane, may have therapeutic values for schizophrenia. The present study investigates the therapeutic effectiveness of low-concentration sevoflurane in MK801-induced schizophrenia-like mice and schizophrenia patients. METHODS: Three weeks after MK801 administration (0.5 mg kg-1, i.p. twice a day for 5 days), mice were exposed to 1% sevoflurane 1hr/day for 5 days. Behavioral tests, immunohistochemical analysis, western blot assay, and electrophysiology assessments were performed 1-week post-exposure. Ten schizophrenia patients received 1% sevoflurane 5 hrs per day for 6 days and were assessed with the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18) at week 1 and week 2. RESULTS: MK801 induced hypolocomotion and social deficits, downregulated expression of NMDARs subunits and postsynaptic density protein 95 (PSD95), reduced parvalbumin - and GAD67-positive neurons, altered amplitude and frequency of mEPSCs and mIPSCs, and increased the excitation/inhibition ratio. All these changes induced by MK-801 were attenuated by sevoflurane administration. Six and eight patients achieved a response defined as a reduction of at least 30% in the PANSS total score at 1st and 2nd week after treatments. The BPRS-18 total score was found to be significantly decreased by 38% at the 2nd week (p < 0.01). CONCLUSION: Low-concentration sevoflurane effectively reversed MK801-induced schizophrenialike disease in mice and alleviated schizophrenia patients' symptoms. Our work suggests sevoflurane to be a valuable therapeutic strategy for treating schizophrenia patients.


Subject(s)
Dizocilpine Maleate , Schizophrenia , Mice , Animals , Sevoflurane/adverse effects , Dizocilpine Maleate/adverse effects , Schizophrenia/chemically induced , Schizophrenia/drug therapy , Feasibility Studies , Neurons
8.
Int J Mol Sci ; 22(22)2021 Nov 13.
Article in English | MEDLINE | ID: mdl-34830164

ABSTRACT

MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or chronic administration of either compound. The present experiments were performed to study the nitric oxide (NO)-related mechanisms underlying memory dysfunction induced by acute or chronic (14 days) administration of MK-801 (0.3 mg/kg, i.p.) or scopolamine (1 mg/kg, i.p.). The levels of L-arginine and its derivatives, L-citrulline, L-glutamate, L-glutamine and L-ornithine, were measured. The expression of constitutive nitric oxide synthases (cNOS), dimethylaminohydrolase (DDAH1) and protein arginine N-methyltransferases (PMRTs) 1 and 5 was evaluated, and the impact of the studied tool compounds on cGMP production and NMDA receptors was measured. The studies were performed in both the cortex and hippocampus of mice. S-nitrosylation of selected proteins, such as GLT-1, APP and tau, was also investigated. Our results indicate that the availability of L-arginine decreased after chronic administration of MK-801 or scopolamine, as both the amino acid itself as well as its level in proportion to its derivatives (SDMA and NMMA) were decreased. Additionally, among all three methylamines, SDMA was the most abundant in the brain (~70%). Administration of either compound impaired eNOS-derived NO production, increasing the monomer levels, and had no significant impact on nNOS. Both compounds elevated DDAH1 expression, and slight decreases in PMRT1 and PMRT5 in the cortex after scopolamine (acute) and MK-801 (chronic) administration were observed in the PFC, respectively. Administration of MK-801 induced a decrease in the cGMP level in the hippocampus, accompanied by decreased NMDA expression, while increased cGMP production and decreased NMDA receptor expression were observed after scopolamine administration. Chronic MK-801 and scopolamine administration affected S-nitrosylation of GLT-1 transport protein. Our results indicate that the analyzed tool compounds used in pharmacological models of schizophrenia or AD induce changes in NO-related pathways in the brain structures involved in cognition. To some extent, the changes resemble those observed in human samples.


Subject(s)
Cerebral Cortex/metabolism , Dizocilpine Maleate/adverse effects , Excitatory Amino Acid Antagonists/adverse effects , Hippocampus/metabolism , Memory Disorders , Nitric Oxide/metabolism , Scopolamine/adverse effects , Animals , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Male , Maze Learning/drug effects , Memory Disorders/chemically induced , Memory Disorders/metabolism , Mice , Scopolamine/pharmacology
9.
J Neurosci Res ; 99(11): 2844-2859, 2021 11.
Article in English | MEDLINE | ID: mdl-34496062

ABSTRACT

Schizophrenia pathophysiology has been associated with dopaminergic hyperactivity, NMDA receptor hypofunction, and redox dysregulation. Most behavioral assays and animal models to study this condition were developed in rodents, leaving room for species-specific biases that could be avoided by cross-species approaches. As MK-801 and amphetamine are largely used in mice and rats to mimic schizophrenia features, this study aimed to compare the effects of these drugs in several zebrafish (Danio rerio) behavioral assays. Male and female adult zebrafish were exposed to MK-801 (1, 5, and 10 µM) or amphetamine (0.625, 2.5, and 10 mg/L) and observed in paradigms of locomotor activity and social behavior. Oxidative parameters were quantified in brain tissue. Our results demonstrate that MK-801 disrupted social interaction, an effect that resembles the negative symptoms of schizophrenia. It also altered locomotion in a context-dependent manner, with hyperactivity when fish were tested in the presence of social cues and hypoactivity when tested alone. On the other hand, exposure to amphetamine was devoid of effects on locomotion and social behavior, while it increased lipid peroxidation in the brain. Key outcomes induced by MK-801 in rodents, such as social interaction deficit and locomotor alterations, were replicated in zebrafish, corroborating previous studies and reinforcing the use of zebrafish to study schizophrenia-related endophenotypes. More studies are necessary to assess the predictive validity of preclinical paradigms with this species and ultimately optimize the screening of potential novel treatments.


Subject(s)
Dizocilpine Maleate , Schizophrenia , Amphetamine/pharmacology , Animals , Dizocilpine Maleate/adverse effects , Endophenotypes , Female , Male , Mice , Rats , Receptors, N-Methyl-D-Aspartate , Schizophrenia/chemically induced , Zebrafish/physiology
10.
Biomed Res Int ; 2021: 1156031, 2021.
Article in English | MEDLINE | ID: mdl-34423030

ABSTRACT

Here, we report the participation of N-methyl-D-aspartate (NMDA) glutamate receptor in the mediation of cardiovascular and circulating vasopressin responses evoked by a hemorrhagic stimulus. In addition, once NMDA receptor activation is a prominent mechanism involved in nitric oxide (NO) synthesis in the brain, we investigated whether control of hemorrhagic shock by NMDA glutamate receptor was followed by changes in NO synthesis in brain supramedullary structures involved in cardiovascular and neuroendocrine control. Thus, we observed that intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK801, 0.3 mg/kg) delayed and reduced the magnitude of hemorrhage-induced hypotension. Besides, hemorrhage induced a tachycardia response in the posthemorrhage period (i.e., recovery period) in control animals, and systemic treatment with MK801 caused a bradycardia response during hemorrhagic shock. Hemorrhagic stimulus increased plasma vasopressin levels during the recovery period and NMDA receptor antagonism increased concentration of this hormone during both the hemorrhage and postbleeding periods in relation to control animals. Moreover, hemorrhagic shock caused a decrease in NOx levels in the paraventricular nucleus of the hypothalamus (PVN), amygdala, bed nucleus of the stria terminalis (BNST), and ventral periaqueductal gray matter (vPAG). Nevertheless, treatment with MK801 did not affect these effects. Taken together, these results indicate that the NMDA glutamate receptor is involved in the hemorrhagic shock by inhibiting circulating vasopressin release. Our data also suggest a role of the NMDA receptor in tachycardia, but not in the decreased NO synthesis in the brain evoked by hemorrhage.


Subject(s)
Bradycardia/chemically induced , Cardiovascular System/metabolism , Dizocilpine Maleate/administration & dosage , Shock, Hemorrhagic/metabolism , Vasopressins/blood , Animals , Bradycardia/blood , Brain/drug effects , Brain/metabolism , Cardiovascular System/drug effects , Disease Models, Animal , Dizocilpine Maleate/adverse effects , Injections, Intraperitoneal , Male , Neurosecretory Systems/drug effects , Neurosecretory Systems/metabolism , Nitric Oxide/metabolism , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism
11.
Behav Brain Res ; 413: 113473, 2021 09 10.
Article in English | MEDLINE | ID: mdl-34280461

ABSTRACT

Schizophrenia is a major psychiatric disease still lacking efficient treatment, particularly for cognitive deficits. To go further in research of new treatments that would encompass all the symptoms associated with this pathology, preclinical animal models need to be improved. To date, the aetiology of schizophrenia is unknown, but there is increasing evidence to highlight its multifactorial nature. We built a new neurodevelopmental mouse model gathering a triple factor combination (3-M): a genetic factor (partial deletion of MAP6 gene), an early stress (maternal separation) and a late pharmacological factor (MK801 administration, 0.05 mg/kg, i.p., daily for 5 days). The effects of each factor and of their combination were investigated on several behaviours including cognitive functions. While each individual factor induced slight deficits in one or another behavioural test, 3-M conditioning induces a wider phenotype with hyperlocomotion and cognitive deficits (working memory and social recognition). This study confirms the hypothesis that genetic, environmental and pharmacological factors, even if not deleterious by themselves, could act synergistically to induce a deleterious behavioural phenotype. It moreover encourages the use of such combined models to improve translational research on neurodevelopmental disorders.


Subject(s)
Behavior, Animal , Cognitive Dysfunction , Dizocilpine Maleate/adverse effects , Excitatory Amino Acid Antagonists/adverse effects , Maternal Deprivation , Microtubule-Associated Proteins/deficiency , Neurodevelopmental Disorders , Stress, Psychological , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/etiology , Cognitive Dysfunction/genetics , Disease Models, Animal , Gene-Environment Interaction , Mice , Microtubule-Associated Proteins/genetics , Neurodevelopmental Disorders/chemically induced , Neurodevelopmental Disorders/etiology , Neurodevelopmental Disorders/genetics , Stress, Psychological/complications
12.
Neurotherapeutics ; 17(3): 1016-1030, 2020 07.
Article in English | MEDLINE | ID: mdl-32632774

ABSTRACT

Neuropathic pain is usually persistent due to maladaptive neuroplasticity-induced central sensitization and, therefore, necessitates long-term treatment. N-methyl-D-aspartate receptor (NMDAR)-mediated hypersensitivity in the spinal dorsal horn represents key mechanisms of central sensitization. Short-term use of NMDAR antagonists produces antinociceptive efficacy in animal pain models and in clinical practice by reducing central sensitization. However, how prolonged use of NMDAR antagonists affects central sensitization remains unknown. Surprisingly, we find that prolonged blockage of NMDARs does not prevent but aggravate nerve injury-induced central sensitization and produce analgesic tolerance, mainly due to reduced synaptic inhibition. The disinhibition that results from the continuous decrease in the production of nitric oxide from neuronal nitric oxide synthase, downstream signal of NMDARs, leads to the reduction of GABAergic inhibitory synaptic transmission by upregulating brain-derived neurotrophic factor expression and inhibiting the expression and function of potassium-chloride cotransporter. Together, our findings suggest that chronic blockage of NMDARs develops analgesic tolerance through the neuronal nitric oxide synthase-brain-derived neurotrophic factor-potassium-chloride cotransporter pathway. Thus, preventing the GABAergic disinhibition induced by nitric oxide reduction may be necessary for the long-term maintenance of the analgesic effect of NMDAR antagonists.


Subject(s)
Analgesics/administration & dosage , Excitatory Amino Acid Antagonists/administration & dosage , GABAergic Neurons/metabolism , Neuralgia/metabolism , Nitric Oxide Synthase Type I/deficiency , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Analgesics/adverse effects , Animals , Dizocilpine Maleate/administration & dosage , Dizocilpine Maleate/adverse effects , Drug Resistance/drug effects , Drug Resistance/physiology , Excitatory Amino Acid Antagonists/adverse effects , GABAergic Neurons/drug effects , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Neural Inhibition/drug effects , Neural Inhibition/physiology , Neuralgia/drug therapy , Neuralgia/genetics , Nitric Oxide/deficiency , Nitric Oxide/genetics , Nitric Oxide Synthase Type I/genetics , Organ Culture Techniques , Rats , Rats, Sprague-Dawley
13.
Pharmacol Biochem Behav ; 193: 172916, 2020 06.
Article in English | MEDLINE | ID: mdl-32220620

ABSTRACT

Schizophrenia is a common psychiatric disease that cannot be fully treated with current antipsychotic drugs. It has shown that glutamatergic NMDA receptor antagonists such as MK-801 cause schizophrenia-like phenotype in rodents. Recent studies indicated that α7 nicotinic acetylcholine receptor (nAChR) deficits contribute to schizophrenia. Enhancing its activity with agonist or positive allosteric modulators (PAMs) may be a valuable approach for treatment. The certain intracellular pathways such as Akt/Glycogen synthase kinase 3 beta (GSK-3ß) and phosphodiesterase-4 (PDE-4)/cAMP are associated with the pathogenesis of schizophrenia. In this study, we examined the effect of α7 nAChR agonists and PAMs on the behavioral and molecular phenotype of schizophrenia in the subchronic MK-801 administered rats. Social interaction, the levels of α7 nAChR, and related intracellular pathways (cAMP, PDE4A, PDE4D, p-Akt/Akt, p-GSK-3ß/GSK-3ß) were measured by behavioral or ELISA and western blot tests. Subchronic MK-801 administration decreased the following behaviors and increased the avoiding behaviors. However, only α7 nAChR agonist (A-582941) increased the following behavior while α7 nAChR agonist, PAMs (CCMI and PNU-120596), and clozapine decreased the avoiding behavior compared to MK-801. For molecular parameters, MK-801 administration decreased the α7 nAChR, p-Akt/Akt, p-GSK-3ß/GSK-3ß expressions, and cAMP levels while it increased PDE4A, PDE4D expressions in the prefrontal cortex. Besides, MK-801 decreased the α7 nAChR, p-GSK-3ß/GSK-3ß expressions in the hippocampus. We found clozapine, α7 nAChR agonists, and PAMs reversed the molecular deficits induced by MK-801. Herein, we showed that prefrontal cortex is more sensitive to the devastating effects of subchronic MK-801 administration, especially for PDE4, in rats. In addition to clozapine, α7 nAChR agonists and PAMs found to be beneficial on both social and molecular deficits induced by MK-801 in rats. We suggested that α7 nAChR agonists and PAMs might be valuable approaches to treat negative symptoms of schizophrenia when unmet needs and current limitations considered in this pathology.


Subject(s)
Clozapine/therapeutic use , Dizocilpine Maleate/adverse effects , Isoxazoles/therapeutic use , Phenylurea Compounds/therapeutic use , Pyridazines/therapeutic use , Pyrroles/therapeutic use , Schizophrenia/chemically induced , Schizophrenia/drug therapy , Signal Transduction/drug effects , Social Interaction/drug effects , alpha7 Nicotinic Acetylcholine Receptor/agonists , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Allosteric Regulation/drug effects , Animals , Avoidance Learning/drug effects , Clozapine/pharmacology , Cyclic AMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Disease Models, Animal , Glycogen Synthase Kinase 3 beta/metabolism , Isoxazoles/pharmacology , Male , Phenylurea Compounds/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pyridazines/pharmacology , Pyrroles/pharmacology , Rats , Rats, Wistar , Treatment Outcome , alpha7 Nicotinic Acetylcholine Receptor/metabolism
14.
Behav Brain Res ; 376: 112228, 2019 12 30.
Article in English | MEDLINE | ID: mdl-31520689

ABSTRACT

Procedural modifications can modulate drug effects in delay discounting, such as signaling the delay to reinforcement and altering the order in which delays are presented. Although the schedule of reinforcement can alter the rate at which animals discount a reinforcer, research has not determined if animals trained on different schedules of reinforcement are differentially affected by pharmacological manipulations. Similarly, research has not determined if using different delays to reinforcement can modulate drug effects in delay discounting. Male Sprague Dawley rats (n = 36) were split into four groups and were trained in a delay-discounting procedure. The schedule of reinforcement (fixed ratio [FR] 1 vs. FR 10) and delays to reinforcement (0, 5, 10, 20, and 50 s vs. 0, 10, 30, 60, 100 s) were manipulated for each group. Following behavioral training, rats were treated with d-amphetamine (0, 0.25, 0.5, and 1.0 mg/kg) and MK-801 (0, 0.03, and 0.06 mg/kg). Results showed that amphetamine decreased impulsive choice when a FR 1 schedule was used, but only when the short delay sequence was used. Conversely, amphetamine decreased impulsive choice when a FR 10 schedule was used, but only when rats were trained on the long delay sequence. MK-801 decreased impulsive choice in rats trained on a FR 1 schedule, regardless of delay sequence, but did not alter choice in rats trained on a FR 10 schedule. These results show that schedule of reinforcement and delay length can modulate drug effects in delay discounting.


Subject(s)
Choice Behavior/drug effects , Delay Discounting/drug effects , Impulsive Behavior/drug effects , Time Factors , Animals , Conditioning, Operant/drug effects , Dextroamphetamine/adverse effects , Dextroamphetamine/pharmacology , Dizocilpine Maleate/adverse effects , Dizocilpine Maleate/pharmacology , Male , Rats , Rats, Sprague-Dawley , Reinforcement Schedule , Reinforcement, Psychology
15.
Pharmacol Res Perspect ; 7(3): e00479, 2019 06.
Article in English | MEDLINE | ID: mdl-31086673

ABSTRACT

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.


Subject(s)
Excitatory Amino Acid Agonists/administration & dosage , Receptors, AMPA/metabolism , Schizophrenia/drug therapy , Thiadiazines/administration & dosage , Animals , Cognition/drug effects , Disease Models, Animal , Dizocilpine Maleate/adverse effects , Drug Evaluation, Preclinical , Excitatory Amino Acid Agonists/pharmacology , Gene Expression Regulation/drug effects , Haplorhini , Male , Maze Learning/drug effects , Methamphetamine/adverse effects , Mice , Phencyclidine , Rats , Schizophrenia/chemically induced , Thiadiazines/chemistry , Thiadiazines/pharmacology
16.
Exp Anim ; 67(2): 163-173, 2018 May 10.
Article in English | MEDLINE | ID: mdl-29225304

ABSTRACT

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.


Subject(s)
Antipsychotic Agents/administration & dosage , Dizocilpine Maleate/adverse effects , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/pharmacology , Haloperidol/administration & dosage , Phytotherapy , Schizophrenia/chemically induced , Schizophrenia/drug therapy , Administration, Oral , Animals , Antipsychotic Agents/pharmacokinetics , Biological Availability , Biological Products , Disease Models, Animal , Drug Synergism , Drug Therapy, Combination , Haloperidol/pharmacokinetics , Male , Rats, Sprague-Dawley
17.
Int J Mol Sci ; 18(3)2017 Feb 24.
Article in English | MEDLINE | ID: mdl-28245567

ABSTRACT

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.


Subject(s)
Brain/metabolism , Dizocilpine Maleate/adverse effects , Flavones/pharmacology , Hyperkinesis/chemically induced , Plant Extracts/pharmacology , Animals , Blood-Brain Barrier/metabolism , Chromatography, High Pressure Liquid , Citrus/chemistry , Flavones/administration & dosage , Flavones/chemistry , Flavones/pharmacokinetics , Hippocampus/metabolism , Hyperkinesis/drug therapy , Injections, Intraperitoneal , MAP Kinase Signaling System/drug effects , Male , Mice , Permeability , Plant Extracts/administration & dosage , Plant Extracts/chemistry , Plant Extracts/pharmacokinetics , Structure-Activity Relationship
18.
Lancet Psychiatry ; 4(3): 208-217, 2017 03.
Article in English | MEDLINE | ID: mdl-28185899

ABSTRACT

BACKGROUND: Cognitive impairment is present in euthymic patients with bipolar disorder and correlates with impairments in everyday functioning. We aimed to examine the efficacy of lurasidone adjunctive therapy compared with treatment as usual (TAU) in improving cognition. METHODS: For this randomised, open-label, pilot study, we recruited patients aged 19-65 years with euthymic bipolar I disorder from the Mood Disorder Centre in UBC Hospital (Vancouver, Canada). We included patients who were taking lithium, or valproate, or an atypical antipsychotic, or a combination of these for mood stabilisation and who showed reduced cognitive functioning (SD≤ -0·25 relative to demographics-corrected norms) on either the Trail Making Test-B or the California Verbal Learning Test-II. Patients were randomly assigned using a randomised block design with a block size of four to TAU or lurasidone adjunctive therapy (20-80 mg/day) for 6 weeks. A research coordinator masked to group allocation administered the International Society for Bipolar Disorders Battery for Assessment of Neurocognition (ISBD-BANC) at baseline and at endpoint. The primary outcome was change in global cognition score, which consisted of the mean demographics-corrected t-score value of the several ISBD-BANC measures, analysed in all patients who completed both tests. This trial is registered on ClinicalTrials.gov, number NCT02147379. FINDINGS: Between July 2, 2014, and Oct 19, 2015, 34 patients were randomly allocated to lurasidone adjunctive therapy (17 patients) or TAU (17 patients). Two patients from each group did not complete the study. The mean lurasidone dose was 48·24 (SD 15·90) mg/day. Lurasidone adjunctive therapy was more effective than TAU in improving the primary efficacy measure of ISBD-BANC global cognition score (mean difference 2·92 [95% CI 0·27-5·57]; time × treatment interaction F=5·09; p=0·032). The between-group effect size (0·82) on baseline versus study-end difference scores in the ISBD global cognition score was of moderate to large magnitude. The magnitude of benefit with lurasidone adjunctive therapy in improving global cognition (effect size 0·46) was greater compared with the improvement observed in the TAU group (0·04). Adverse events were reported by nine (60%) patients in the luradisone group and two (13%) in the TAU group. INTERPRETATION: Our results provide some preliminary evidence for the efficacy of lurasidone in improving cognition in euthymic patients with bipolar I disorder. The strengths of this study were the characterisation of the sample and use of tests sensitive to cognitive impairment in bipolar disorder. Its limitations were the sample size and inability to completely control for other medication use. Larger double-blind trials are warranted to investigate this further. FUNDING: Sumitomo Dainippon Pharma.


Subject(s)
Cognition/drug effects , Cognitive Dysfunction/drug therapy , Drug Therapy, Combination/methods , Lurasidone Hydrochloride/therapeutic use , Adult , Aged , Antipsychotic Agents/therapeutic use , Canada/epidemiology , Cholinergic Antagonists/adverse effects , Cognitive Dysfunction/chemically induced , Dizocilpine Maleate/adverse effects , Female , Humans , Lurasidone Hydrochloride/administration & dosage , Male , Middle Aged , Neuroprotective Agents/adverse effects , Scopolamine/adverse effects , Serotonin 5-HT2 Receptor Antagonists/therapeutic use , Treatment Outcome
19.
J Psychopharmacol ; 31(2): 250-259, 2017 02.
Article in English | MEDLINE | ID: mdl-27729563

ABSTRACT

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.


Subject(s)
Apigenin/pharmacology , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy , Dizocilpine Maleate/adverse effects , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Acoustic Stimulation/methods , Animals , Cognitive Dysfunction/metabolism , Flavonoids/pharmacology , Glycogen Synthase Kinase 3/metabolism , Male , Memory Disorders/metabolism , Mice , Mice, Inbred ICR , Phosphorylation/drug effects , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Reflex, Startle/drug effects , Schizophrenia/chemically induced , Schizophrenia/drug therapy , Schizophrenia/metabolism , Sensory Gating/drug effects , Signal Transduction/drug effects
20.
Chem Biol Drug Des ; 89(3): 353-364, 2017 03.
Article in English | MEDLINE | ID: mdl-27543496

ABSTRACT

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.


Subject(s)
Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Flavanones/chemistry , Animals , Antipsychotic Agents/chemical synthesis , Apomorphine/adverse effects , Apomorphine/pharmacology , Chemistry Techniques, Synthetic , Disease Models, Animal , Dizocilpine Maleate/adverse effects , Dizocilpine Maleate/pharmacology , Drug Evaluation, Preclinical/methods , HEK293 Cells/drug effects , Humans , Male , Mice, Inbred BALB C , Microglia/drug effects , Microglia/metabolism , Nitric Oxide/metabolism , Receptors, Dopamine D2/metabolism , Schizophrenia/chemically induced , Schizophrenia/drug therapy
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