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International Journal of Molecular... Mar 2023Cognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive...
Cognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive deficits in hypoglutamatergic states such as schizophrenia, although little is known about how POP inhibitors exert their pharmacological activity. The mitochondrial and nuclear protein Prohibitin 2 (PHB2) could be dysregulated in schizophrenia. However, altered PHB2 levels in schizophrenia linked to N-methyl-D-aspartate receptor (NMDAR) activity and cognitive deficits are still unknown. To shed light on this, we measured the PHB2 levels by immunoblot in a postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects, in the frontal pole of mice treated with the NMDAR antagonists phencyclidine and dizocilpine, and in rat cortical astrocytes and neurons treated with dizocilpine. Mice and cells were treated in combination with the POP inhibitor IPR19. The PHB2 levels were also analyzed by immunocytochemistry in rat neurons. The PHB2 levels increased in DLPFC in cases of chronic schizophrenia and were associated with cognitive impairments. NMDAR antagonists increased PHB2 levels in the frontal pole of mice and in rat astrocytes and neurons. High levels of PHB2 were found in the nucleus and cytoplasm of neurons upon NMDAR inhibition. IPR19 restored PHB2 levels in the acute NMDAR inhibition. These results show that IPR19 restores the upregulation of PHB2 in an acute NMDAR hypoactivity stage suggesting that the modulation of PHB2 could compensate NMDAR-dependent cognitive impairments in schizophrenia.
Topics: Animals; Rats; Cognition; Cognitive Dysfunction; Dizocilpine Maleate; Prohibitins; Prolyl Oligopeptidases; Psychotic Disorders; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 37046989
DOI: 10.3390/ijms24076016 -
ACS Pharmacology & Translational Science Jan 2023We have developed and characterized a novel D2R antagonist with exceptional GPCR selectivity - ML321. In functional profiling screens of 168 different GPCRs, ML321...
Identification and Characterization of ML321: A Novel and Highly Selective D Dopamine Receptor Antagonist with Efficacy in Animal Models That Predict Atypical Antipsychotic Activity.
We have developed and characterized a novel D2R antagonist with exceptional GPCR selectivity - ML321. In functional profiling screens of 168 different GPCRs, ML321 showed little activity beyond potent inhibition of the D2R and to a lesser extent the D3R, demonstrating excellent receptor selectivity. The D2R selectivity of ML321 may be related to the fact that, unlike other monoaminergic ligands, ML321 lacks a positively charged amine group and adopts a unique binding pose within the orthosteric binding site of the D2R. PET imaging studies in non-human primates demonstrated that ML321 penetrates the CNS and occupies the D2R in a dose-dependent manner. Behavioral paradigms in rats demonstrate that ML321 can selectively antagonize a D2R-mediated response (hypothermia) while not affecting a D3R-mediated response (yawning) using the same dose of drug, thus indicating exceptional selectivity. We also investigated the effects of ML321 in animal models that are predictive of antipsychotic efficacy in humans. We found that ML321 attenuates both amphetamine- and phencyclidine-induced locomotor activity and restored pre-pulse inhibition (PPI) of acoustic startle in a dose-dependent manner. Surprisingly, using doses that were maximally effective in both the locomotor and PPI studies, ML321 was relatively ineffective in promoting catalepsy. Kinetic studies revealed that ML321 exhibits slow-on and fast-off receptor binding rates, similar to those observed with atypical antipsychotics with reduced extrapyramidal side effects. Taken together, these observations suggest that ML321, or a derivative thereof, may exhibit ″atypical″ antipsychotic activity in humans with significantly fewer side effects than observed with the currently FDA-approved D2R antagonists.
PubMed: 36654757
DOI: 10.1021/acsptsci.2c00202 -
International Journal of Molecular... Aug 2022NX210c is a disease-modifying dodecapeptide derived from the subcommissural organ-spondin that is under preclinical and clinical development for the treatment of...
NX210c is a disease-modifying dodecapeptide derived from the subcommissural organ-spondin that is under preclinical and clinical development for the treatment of neurological disorders. Here, using whole-cell patch-clamp recordings, we demonstrate that NX210c increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and GluN2A-containing N-methyl-D-aspartate receptor (GluN2A-NMDAR)-mediated excitatory postsynaptic currents in the brain. Accordingly, using extracellular field excitatory postsynaptic potential recordings, an enhancement of synaptic transmission was shown in the presence of NX210c in two different neuronal circuits. Furthermore, the modulation of synaptic transmission and GluN2A-NMDAR-driven signaling by NX210c restored memory in mice chronically treated with the NMDAR antagonist phencyclidine. Overall, by promoting glutamatergic receptor-related neurotransmission and signaling, NX210c represents an innovative therapeutic opportunity for patients suffering from CNS disorders, injuries, and states with crippling synaptic dysfunctions.
Topics: Animals; Central Nervous System; Excitatory Postsynaptic Potentials; Mice; Peptides; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission
PubMed: 36012124
DOI: 10.3390/ijms23168867 -
Journal of Neurosurgery. Case Lessons Mar 2022The incidence of pain-generating degenerative spinal problems in patients who are currently using or have previously used drugs has increased as substance use disorder...
BACKGROUND
The incidence of pain-generating degenerative spinal problems in patients who are currently using or have previously used drugs has increased as substance use disorder (SUD) becomes a chronic, lifelong condition. Health system-level data in recent years indicate a significant increase in patients with coexisting SUD and degenerative disc disease, representing an emerging population. A retrospective electronic medical record review identified seven patients with SUD who underwent elective spine surgery by orthopedic or neurosurgical staff from 2012 to 2021. The authors present two of these illustrative cases and a framework that can be used in the treatment of similar patients.
OBSERVATIONS
Substances used included opioids, benzodiazepines, barbiturates, cocaine, methamphetamines, hallucinogens, lysergic acid diethylamide, phencyclidine, and cannabis. All were abstaining from drug use preoperatively, with four patients in a formal treatment program. Five patients were discharged with an opioid prescription, and two patients deferred opioids. Three experienced a relapse of substance use within 1 year. All patients presented for follow-up, although two required additional contact for follow-up compliance.
LESSONS
Perioperative protocols focusing on patient-led care plans, pain control, communication with medication for opioid use disorder providers, family and social support, and specific indicators of possible poor results can contribute to better outcomes for care challenges associated with these diagnoses.
PubMed: 36273856
DOI: 10.3171/CASE21656 -
British Journal of Pharmacology Jul 2020Hispidulin is a flavonoid isolated from Clerodendrum inerme that was found to inhibit intractable motor tics. Previously, we found that hispidulin attenuates...
BACKGROUND AND PURPOSE
Hispidulin is a flavonoid isolated from Clerodendrum inerme that was found to inhibit intractable motor tics. Previously, we found that hispidulin attenuates hyperlocomotion and the disrupted prepulse inhibition induced by methamphetamine and N-methyl-d-aspartate (NMDA) receptor antagonists, two phenotypes of schizophrenia resembling positive symptoms. Hispidulin can inhibit COMT, a dopamine-metabolizing enzyme in the prefrontal cortex (PFC) that is important for social interaction. Here, we investigated whether hispidulin would affect social withdrawal, one of the negative symptoms of schizophrenia.
EXPERIMENTAL APPROACH
We examined whether acute administration of hispidulin would attenuate social withdrawal in two mice models, juvenile isolated disrupted-in-schizophrenia-1 mutant (mutDISC1) mice and chronic phencyclidine (PCP)-treated naïve mice.
KEY RESULTS
In chronic PCP-treated mice, hispidulin (10 mg·kg , i.p.) attenuated social withdrawal similar to that observed with dopamine D receptor antagonist (SCH-23390, 0.02 mg·kg , i.p.) and was mimicked by the selective COMT inhibitor, OR-486 (10 mg·kg , i.p.). Hispidulin increased extracellular dopamine levels in the PFC of chronic PCP-treated mice. In isolated mutDISC1 mice, hispidulin also reversed social withdrawal. In both models, intra-PFC microinjection of a D agonist (SKF-81297: 10 nmol/mouse/bilateral) reversed the impairment of Ser phosphorylation at the GluN1 subunit of NMDA receptors, suggesting the association between GluN1 Ser -phosphorylation and D activation in the PFC exits in both models.
CONCLUSIONS AND IMPLICATIONS
Hispidulin attenuated social withdrawal by activating D receptors indirectly through elevated dopamine levels in the PFC by COMT inhibition. This nature of hispidulin suggests that it a potential novel therapeutic candidate for the treatment of negative symptoms in schizophrenia.
Topics: Animals; Flavones; Mice; Phencyclidine; Prefrontal Cortex; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Social Isolation
PubMed: 32133633
DOI: 10.1111/bph.15043 -
Biological Psychiatry Sep 2021Polymorphisms in GRM3, the gene encoding the mGlu metabotropic glutamate receptor, are associated with impaired cognition and neuropsychiatric disorders such as...
BACKGROUND
Polymorphisms in GRM3, the gene encoding the mGlu metabotropic glutamate receptor, are associated with impaired cognition and neuropsychiatric disorders such as schizophrenia. Limited availability of selective genetic and molecular tools has hindered progress in developing a clear understanding of the mechanisms through which mGlu receptors regulate synaptic plasticity and cognition.
METHODS
We examined associative learning in mice with trace fear conditioning, a hippocampal-dependent learning task disrupted in patients with schizophrenia. Underlying cellular mechanisms were assessed using ex vivo hippocampal slice preparations with selective pharmacological tools and selective genetic deletion of mGlu receptor expression in specific neuronal subpopulations.
RESULTS
mGlu receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through an mGlu receptor-dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu or mGlu from hippocampal pyramidal cells eliminated effects of mGlu activation, revealing a novel mechanism by which mGlu and mGlu interact to enhance cognitive function.
CONCLUSIONS
These data demonstrate that activation of mGlu receptors in hippocampal pyramidal cells enhances hippocampal-dependent cognition in control and impaired mice by inducing a novel form of metaplasticity to regulate circuit function, providing a clear mechanism through which genetic variation in GRM3 can contribute to cognitive deficits. Developing approaches to positively modulate mGlu receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases.
Topics: Animals; Cognition; Hippocampus; Long-Term Potentiation; Mice; Receptors, Metabotropic Glutamate; Schizophrenia
PubMed: 33965197
DOI: 10.1016/j.biopsych.2021.02.970 -
Behavioural Pharmacology Aug 2019Ultrasonic vocalizations are widely used to examine affective states in rats, yet relatively few studies explore the acoustic features of vocalizations, especially in...
Ultrasonic vocalizations are widely used to examine affective states in rats, yet relatively few studies explore the acoustic features of vocalizations, especially in relation to drug exposure, and no studies have explored alterations in acoustic features over time. The goal of this study was to examine nicotine- and phencyclidine-induced alterations of bandwidth, duration, and frequency of 50 kHz vocalizations. The minimum and maximum frequency, bandwidth, and duration of calls were examined after 7 days of daily subcutaneous administration of phencyclidine (2.0 mg/kg) and nicotine (0.2 and 0.4 mg/kg) in male Sprague-Dawley rats. Bandwidth was significantly decreased in rats treated with both nicotine (0.2 and 0.4 mg/kg) and phencyclidine. Maximum frequency was lowest on the first day of exposure compared with all other days and was not altered by drug exposure. Call duration was not affected by time or drug exposure. These findings suggest the importance of studying alterations in acoustic features in time, especially those induced by drug exposure.
Topics: Acoustics; Animals; Male; Nicotine; Phencyclidine; Rats; Rats, Sprague-Dawley; Ultrasonics; Vocalization, Animal
PubMed: 30801260
DOI: 10.1097/FBP.0000000000000463 -
Radiology Case Reports Oct 2023Cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome is a constellation of specific imaging findings characterized by...
Cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome is a constellation of specific imaging findings characterized by cytotoxic edema in the bilateral hippocampi, cerebellar cortices, and basal ganglia in patients presenting with altered mental status in the setting of substance intoxication. Previous case reports have demonstrated a strong correlation between CHANTER syndrome and polysubstance abuse, particularly with opioid intoxication. The patient we present in this case was found unresponsive following opioid use and demonstrated a constellation of findings on initial and follow-up imaging, consistent with CHANTER syndrome. While cases of irreversible brain damage or death during hospitalization have been reported in the literature, our patient demonstrated near-full recovery a few days after admission to the hospital. We aim to highlight the presentation and progression of CHANTER syndrome and alert clinicians and radiologists to include this entity in their diagnostic checklist for patients with polysubstance abuse and altered mental status.
PubMed: 37554665
DOI: 10.1016/j.radcr.2023.07.015 -
International Journal of Molecular... Aug 2021Major depressive disorder is a disabling disease with the number of affected individuals increasing each year. Current antidepressant treatments take between three to...
Major depressive disorder is a disabling disease with the number of affected individuals increasing each year. Current antidepressant treatments take between three to six weeks to be effective with forty percent of patients being resistant to treatment, making it necessary to search for new antidepressant treatments. Ketamine, a phencyclidine hydrochloride derivative, given intravenously, induces a rapid antidepressant effect in humans. In mice, it causes increased neurogenesis and antidepressant-like effects. However, it also produces psychomimetic effects in humans and in rodents increases the locomotor activity. In contrast, melatonin, a hormone secreted by the pineal gland and synthesized in extrapineal sites, increases new neuron formation and causes antidepressant-like effects in adult rodents with no collateral effects. Here, we assessed the effects of a non-effective dose of ketamine in combination with melatonin (KET/MEL), both on neurogenesis as well as on the antidepressant-like effect in mice. Our results showed that KET/MEL combination increased neurogenesis and produced antidepressant-like effects without altering locomotor activity after both single and triple administration protocols. Our data strongly suggest that KET/MEL combination could be used to simultaneously promote neurogenesis, reverting neuronal atrophy and inducing antidepressant-like effects.
Topics: Animals; Antidepressive Agents; Depression; Drug Combinations; Drug Synergism; Ketamine; Male; Melatonin; Mice; Neurogenesis
PubMed: 34502152
DOI: 10.3390/ijms22179225 -
Current Neuropharmacology 2024The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present...
The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.
Topics: Rats; Mice; Animals; Antipsychotic Agents; Schizophrenia; Apomorphine; Hydroxybenzoate Ethers; Disease Models, Animal; Cognition
PubMed: 37475559
DOI: 10.2174/1570159X21666230720122354