Andrographolide improves PCP-induced schizophrenia-like behaviors through blocking interaction between NRF2 and KEAP1.

Schizophrenia is one of the foremost psychological illness around the world, and recent evidence shows that inflammation and oxidative stress may play a critical role in the etiology of schizophrenia. Andrographolide is a diterpenoid lactone from Andrographis paniculate, which has shown anti-inflammation and anti-oxidative effects. In this study, we explored whether andrographolide can improve schizophrenia-like behaviors through its inhibition of inflammation and oxidative stress in Phencyclidine (PCP)-induced mouse model of schizophrenia. We found that abnormal behavioral including locomotor activity, forced swimming and novel object recognition were ameliorated following andrographolide administration (5 mg/kg and 10 mg/kg). Andrographolide inhibited PCP-induced production of inflammatory cytokines, decreased p-p65, p-IκBα, p-p38 and p-ERK1/2 in the prefrontal cortex. Andrographolide significantly declined the level of MDA and GSH, as well as elevated the activity of SOD, CAT and GCH-px. In addition, andrographolide increased expression of NRF-2, HO-1 and NQO-1, promoted nuclear translocation of NRF-2 through blocking the interaction between NRF-2 and KEAP1, which may be associated with directly binding to NRF-2. Furthermore, antioxidative effects and anti-schizophrenia-like behaviors of andrographolide were compromised by the application of NRF-2 inhibitor ML385. In conclusion, these results suggested that andrographolide improved oxidative stress and schizophrenia-like behaviors induced by PCP through increasing NRF-2 pathway.

Neurological, sensorimotor and cardiorespiratory alterations induced by methoxetamine, ketamine and phencyclidine in mice.

Novel psychoactive substances are intoxicating compounds developed to mimic the effects of well-established drugs of abuse. They are not controlled by the United Nations drug convention and pose serious health concerns worldwide. Among them, the dissociative drug methoxetamine (MXE) is structurally similar to ketamine (KET) and phencyclidine (PCP) and was created to purposely mimic the psychotropic effects of its "parent" compounds. Recent animal studies show that MXE is able to stimulate the mesolimbic dopaminergic transmission and to induce KET-like discriminative and rewarding effects. In light of the renewed interest in KET and PCP analogs, we decided to deepen the investigation of MXE-induced effects by a battery of behavioral tests widely used in studies of "safety-pharmacology" for the preclinical characterization of new molecules. To this purpose, the acute effects of MXE on neurological and sensorimotor functions in mice, including visual, acoustic and tactile responses, thermal and mechanical pain, motor activity and acoustic startle reactivity were evaluated in comparisons with KET and PCP to better appreciate its specificity of action. Cardiorespiratory parameters and blood pressure were also monitored in awake and freely moving animals. Acute systemic administrations of MXE, KET and PCP (0.01-30 mg/kg i.p.) differentially alter neurological and sensorimotor functions in mice depending in a dose-dependent manner specific for each parameter examined. MXE and KET (1 and 30 mg/kg i.p.) and PCP (1 and 10 mg/kg i.p.) also affect significantly cardiorespiratory parameters, systolic and diastolic blood pressure in mice.

Ginsenoside Re protects against phencyclidine-induced behavioral changes and mitochondrial dysfunction via interactive modulation of glutathione peroxidase-1 and NADPH oxidase in the dorsolateral cortex of mice.

We investigated whether ginsenoside Re (Re) modulates phencyclidine (PCP)-induced sociability deficits and recognition memory impairments to extend our recent finding. We examined the role of GPx-1 gene in the pharmacological activity of Re against mitochondrial dysfunction induced by PCP in the dorsolateral cortex of mice. Since mitochondrial oxidative stress activates NADPH oxidase (PHOX), we applied PHOX inhibitor apocynin for evaluating interactive modulation between GPx-1 and PHOX against PCP neurotoxicity. Sociability deficits and recognition memory impairments induced by PCP were more pronounced in GPx-1 knockout (KO) than in wild type (WT) mice. PCP-induced mitochondrial oxidative stress, mitochondrial dysfunction, and membrane translocation of p47phox were more evident in GPx-1 KO than in WT. Re treatment significantly attenuated PCP-induced neurotoxic changes. Re also significantly attenuated PCP-induced sociability deficits and recognition memory impairments. The attenuation by Re was comparable to that by apocynin. The attenuation was more obvious in GPx-1 KO than in WT. Importantly, apocynin did not show any additional positive effects on the neuroprotective activity of Re, indicating that PHOX is a molecular target for therapeutic activity of Re. Our results suggest that Re requires interactive modulation between GPx activity and PHOX (p47phox) to exhibit neuroprotective potentials against PCP insult.

"Trip-Sitting" in the Black Hole: A Netnographic Study of Dissociation and Indigenous Harm Reduction.

An array of dissociative novel psychoactive substances, including "methoxetamine," "3-MeO-PCP," and "methoxphenidine," have emerged as substitutes for the illicit substance "ketamine." A netographic research methodology aimed to describe online, dissociative novel psychoactive substance users' perceptions of risk, informed knowledge around use, and indigenous harm-reduction practices as advocated within online drug fora, so as to provide credible information which can be used to inform public online health education and drug prevention. Systematic Internet searches were performed using the terms "synthetic dissociative," "methoxetamine," "methoxphenidine," "diphenidine," "3-MeO-PCP," "4-MeO-PCP," "2-MDP," and "dissociative research chemical" in combination with "forum." Following screening of 3,476 forum threads with removal of duplicates and exclusion criteria, 90 user trip reports and 115 fora threads from seven drug fora websites were analyzed by conducting content analysis. Five themes emerged with 43 categories. The findings illustrated how forum activity within the cyber drug user community disseminated and exchanged "communal folk pharmacology" relating to the use of dissociative novel psychoactive substances. Further research and consistent monitoring of Internet drug fora are advised to explore variations in harm-reduction tactics throughout dissociative NPS populations, and to consider how existing harm-reduction initiatives are influencing these hard-to-reach groups.

Cognitive enhancement effects of Bacopa monnieri (Brahmi) on novel object recognition and NMDA receptor immunodensity in the prefrontal cortex and hippocampus of sub-chronic phencyclidine rat model of schizophrenia.

BACKGROUND: Cognitive impairment is a common characteristic in schizophrenia that cannot be attenuated by antipsychotics. Brahmi, popularly known as a cognitive enhancer might be a new frontier of cognitive deficit treatment in schizophrenia. OBJECTIVE: To study effects of Brahmi on attenuation at cognitive deficit and cerebral glutamate/N-methyl-D-aspartate (NMDA) receptor density in sub-chronic phencyclidine (PCP) rat model of schizophrenia. MATERIAL AND METHOD: Rats were administered PCP or vehicle. Half of the PCP-group was treated with Brahmi. Discrimination ratio (DR) representing cognitive ability was obtained from novel object recognition task. NMDA immunodensity was measured in prefrontal cortex, striatum, cornu ammonis fields 1 to 3 of hippocampus (CA1-3), and dentate gyrus (DG) using immunohistochemistry. RESULTS: DR in PCP-group was significantly decreased compared with control. This occurred alongside NMDA up-regulation in prefrontal cortex and CA1-3, but not in striatum and DG. PCP with Brahmi showed a significant increase in DR score compared with PCP alone. This occurred alongside significant decrease in NMDA immunodensity in prefrontal cortex and CA1-3. No significant difference in cerebral NMDA immunodensity was observed between PCP with Brahmi and control. CONCLUSION: Cognitive deficit observed in PCP-administered rats was mediated by NMDA up-regulation in prefrontal cortex and CA1-3. Interestingly, Brahmi could recover this cognitive deficit by decreasing NMDA density in these brain areas to normal.

Prenatal NMDA receptor antagonism impaired proliferation of neuronal progenitor, leading to fewer glutamatergic neurons in the prefrontal cortex.

N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression.

Chronic phencyclidine administration induces schizophrenia-like changes in N-acetylaspartate and N-acetylaspartylglutamate in rat brain.

Administration of phencyclidine (PCP) to both humans and animals models the symptoms of schizophrenia. Brain concentrations of N-acetylaspartate (NAA) are reduced in this disease, reflecting neuronal dysfunction. This study investigates the effects in rats of a chronic intermittent regime of PCP on NAA and its precursor N-acetylaspartylglutamate (NAAG) in rat frontal and temporal cortex, hippocampus and striatum, determined by HPLC. We found significant PCP-induced deficits of NAA and NAAG only in the temporal cortex; NAAG was significantly elevated in the hippocampus. These changes closely reflect postmortem findings reported in schizophrenia.

Evaluación preliminar de los efectos neurofarmacológicos de Justicia pectoris / Preliinary evaluation of neuropharmacological effects of Justicia pectoris

Se realizaron ensayos preliminares de la decocción de Justicia pectoralis en ratones de la cepa C-57, donde se evaluaron los posible efectos de dichas decocciones sobre la conducta exploratoria, la conducta agresiva y las convulsiones inducidas por pentilentetrazol en ratones. También se estudió el efecto de J. pectoralis sobre la excitación producida por fenciclidina (droga esquizofrenomimética) en ratas infantiles. Los resultados obtenidos sugieren que Justicia pectoralis reduce la conducta agresiva y la actividad exploratoria en ratones, bloquea la excitación inducida por fenciclidina en ratas infantiles y no previene las convulsiones inducidas por pentilentetrazol

Evaluación preliminar de los efectos neurofarmacológicos de Justicia pectoris / Preliminary evaluation of neuropharmacological effects of Justicia pectoris

Se realizaron ensayos preliminares de la decocción de Justicia pectoralis en ratones de la cepa C-57, donde se evaluaron los posible efectos de dichas decocciones sobre la conducta exploratoria, la conducta agresiva y las convulsiones inducidas por pentilentetrazol en ratones. También se estudió el efecto de J. pectoralis sobre la excitación producida por fenciclidina (droga esquizofrenomimética) en ratas infantiles. Los resultados obtenidos sugieren que Justicia pectoralis reduce la conducta agresiva y la actividad exploratoria en ratones, bloquea la excitación inducida por fenciclidina en ratas infantiles y no previene las convulsiones inducidas por pentilentetrazol