scholarly journals Towards Novel Treatments for Schizophrenia: Molecular and Behavioural Signatures of the Psychotropic Agent SEP-363856

2021 ◽  
Vol 22 (8) ◽  
pp. 4119
Author(s):  
Veronica Begni ◽  
Alice Sanson ◽  
Alessia Luoni ◽  
Federica Sensini ◽  
Ben Grayson ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Brain Regions ◽  
Phase Iii ◽  
Acute Administration ◽  
Adult Rats ◽  
Novel Treatments ◽  
Psychotropic Agent ◽  
Behavioural Activity ◽  
Acute Injection ◽  
Induced Changes

Schizophrenia is a complex psychopathology whose treatment is still challenging. Given the limitations of existing antipsychotics, there is urgent need for novel drugs with fewer side effects. SEP-363856 (SEP-856) is a novel psychotropic agent currently under phase III clinical investigation for schizophrenia treatment. In this study, we investigated the ability of an acute oral SEP-856 administration to modulate the functional activity of specific brain regions at basal levels and under glutamatergic or dopaminergic-perturbed conditions in adult rats. We found that immediate-early genes (IEGs) expression was strongly upregulated in the prefrontal cortex and, to a less extent, in the ventral hippocampus, suggesting an activation of these regions. Furthermore, SEP-856 was effective in preventing the hyperactivity induced by an acute injection of phencyclidine (PCP), but not of d-amphetamine (AMPH). The compound effectively normalized the PCP-induced increase in IEGs expression in the PFC at all doses tested, whereas only the highest dose determined the major modulations on AMPH-induced changes. Lastly, SEP-856 acute administration corrected the cognitive deficits produced by subchronic PCP administration. Taken together, our data provide further insights on SEP-856, suggesting that modulation of the PFC may represent an important mechanism for the functional and behavioural activity of this novel compound.

Lesions of hypothalamic PVN partially attenuate stimulatory action of alcohol on ACTH secretion in rats

1994 ◽  
Vol 266 (2) ◽  
pp. R553-R558 ◽  
Author(s):  
S. Rivest ◽  
C. Rivier
Keyword(s):  
Brain Regions ◽  
Acute Administration ◽  
Mrna Levels ◽  
Acth Secretion ◽  
Stimulatory Action ◽  
Acute Injection ◽  
Bilateral Lesions ◽  
Acth Release

We have previously shown that the ability of alcohol to stimulate adrenocorticotropic hormone (ACTH) secretion was significantly blunted by immunoneutralization of endogenous corticotropin-releasing factor (CRF) and that long-term exposure to alcohol increased CRF mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus. In the present study, we further investigated the participating role of the PVN by studying the effect of bilateral lesions of the PVN on alcohol-induced ACTH release. The acute injection of alcohol (1.5 g/kg ip) induced significant increases in plasma ACTH levels in sham-operated animals. Lesions of the PVN attenuated this response but did not abolish it. Indeed, lesioned rats retained significantly elevated ACTH values despite removal of secretagogues of PVN origin. Because removal of hypothalamic CRF can alter ACTH secretion in response to secretagogues, we studied possible changes in pituitary responsiveness to CRF. The results failed to indicate that hyperresponsiveness of the corticotrophs played a major role in accounting for the residual ACTH release of lesioned rats after alcohol treatment. We conclude that brain regions other than the PVN can modulate ACTH release during acute administration of alcohol.

scholarly journals Monoclonal Antibodies Targeting CGRP: From Clinical Studies to Real-World Evidence—What Do We Know So Far?

2021 ◽  
Vol 14 (7) ◽  
pp. 700
Author(s):  
Theodoros Mavridis ◽  
Christina I. Deligianni ◽  
Georgios Karagiorgis ◽  
Ariadne Daponte ◽  
Marianthi Breza ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Real World ◽  
Large Scale ◽  
Randomized Clinical Trials ◽  
Clinical Investigation ◽  
Phase Iii ◽  
Real World Evidence ◽  
Symptomatic Management ◽  
Repurposed Drugs ◽  
Cephalic Pain

Now more than ever is the time of monoclonal antibody use in neurology. In headaches, disease-specific and mechanism-based treatments existed only for symptomatic management of migraines (i.e., triptans), while the standard prophylactic anti-migraine treatments consist of non-specific and repurposed drugs that share limited safety profiles and high risk for interactions with other medications, resulting in rundown adherence rates. Recent advances in headache science have increased our understanding of the role of calcitonin gene relate peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) pathways in cephalic pain neurotransmission and peripheral or central sensitization, leading to the development of monoclonal antibodies (mAbs) or small molecules targeting these neuropeptides or their receptors. Large scale randomized clinical trials confirmed that inhibition of the CGRP system attenuates migraine, while the PACAP mediated nociception is still under scientific and clinical investigation. In this review, we provide the latest clinical evidence for the use of anti-CGRP in migraine prevention with emphasis on efficacy and safety outcomes from Phase III and real-world studies.

scholarly journals β-Elemene Suppresses Obesity-Induced Imbalance in the Microbiota-Gut-Brain Axis

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 704
Author(s):  
Yingyu Zhou ◽  
Wanyi Qiu ◽  
Yimei Wang ◽  
Rong Wang ◽  
Tomohiro Takano ◽  
...  
Keyword(s):  
Intestinal Microbiota ◽  
High Fat Diet ◽  
Brain Regions ◽  
Cerebral Metabolites ◽  
The Central Nervous System ◽  
Cerebral Inflammation ◽  
Regulatory Effects ◽  
Induced Changes ◽  
Pearson Correlations ◽  
Glucose Cycle

As a kind of metabolically triggered inflammation, obesity influences the interplay between the central nervous system and the enteral environment. The present study showed that β-elemene, which is contained in various plant substances, had effects on recovering the changes in metabolites occurring in high-fat diet (HFD)-induced obese C57BL/6 male mice brains, especially in the prefrontal cortex (PFC) and hippocampus (HIP). β-elemene also partially reversed HFD-induced changes in the composition and contents of mouse gut bacteria. Furthermore, we evaluated the interaction between cerebral metabolites and intestinal microbiota via Pearson correlations. The prediction results suggested that Firmicutes were possibly controlled by neuron integrity, cerebral inflammation, and neurotransmitters, and Bacteroidetes in mouse intestines might be related to cerebral aerobic respiration and the glucose cycle. Such results also implied that Actinobacteria probably affected cerebral energy metabolism. These findings suggested that β-elemene has regulatory effects on the imbalanced microbiota-gut-brain axis caused by obesity and, therefore, would contribute to the future study in on the interplay between cerebral metabolites from different brain regions and the intestinal microbiota of mice.

Structural and Functional MRI Brain Changes in Patients with Schizophrenia Following Electroconvulsive Therapy: A Systematic Review

2021 ◽  
Vol 19 ◽  
Author(s):  
Yuchao Jiang ◽  
Mingjun Duan ◽  
Hui He ◽  
Dezhong Yao ◽  
Cheng Luo
Keyword(s):  
Systematic Review ◽  
Functional Mri ◽  
Electroconvulsive Therapy ◽  
Brain Regions ◽  
Parahippocampal Gyrus ◽  
Medical Subject Headings ◽  
Therapeutic Mechanisms ◽  
Brain Changes ◽  
Meta Analyses ◽  
Induced Changes

Background: Schizophrenia (SZ) is a severe psychiatric disorder typically characterized by multidimensional psychotic syndromes. Electroconvulsive therapy (ECT) is a treatment option for medication-resistant patients with SZ or to resolve acute symptoms. Although the efficacy of ECT has been demonstrated in clinical use, its therapeutic mechanisms in the brain remain elusive. Objective: This study aimed to summarize brain changes on structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) after ECT. Methods: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was carried out. The PubMed and Medline databases were systematically searched using the following medical subject headings (MeSH): (electroconvulsive therapy OR ECT) AND (schizophrenia) AND (MRI OR fMRI OR DTI OR DWI). Results: This review yielded 12 MRI studies, including 4 with sMRI, 5 with fMRI and 3 with multimodal MRI. Increases in volumes of the hippocampus and its adjacent regions (parahippocampal gyrus and amygdala) as well as insula and frontotemporal regions were noted after ECT. fMRI studies found ECT-induced changes in different brain regions/networks, including the hippocampus, amygdala, default model network, salience network and other regions/networks that are thought to highly correlate with the pathophysiologic characteristics of SZ. The results of the correlation between brain changes and symptom remissions are inconsistent Conclusion: Our review provides evidence supporting ECT-induced brain changes on sMRI and fMRI in SZ and explores the relationship between these changes and symptom remission.

EXTH-49. FOCUSED ULTRASOUND AND 5-ALA MEDIATED ELIMINATION OF DIFFUSE MIDLINE GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi174-vi174
Author(s):  
Luana Schaab ◽  
Yann Ferry ◽  
Mehmet Ozdas ◽  
Bettina Kritzer ◽  
Sulayman Mourabit ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Focused Ultrasound ◽  
Aminolevulinic Acid ◽  
Clinical Investigation ◽  
Protoporphyrin Ix ◽  
Brain Regions ◽  
Sonodynamic Therapy ◽  
Diffuse Infiltration ◽  
Rat Glioma ◽  
Diffuse Midline Glioma

Abstract Diffuse midline glioma (DMG) is a devastating and incurable childhood brain cancer. With a median survival of only 9 to 11 months, over 90% of children affected by DMG die within two years of diagnosis. Despite decades of research and a growing understanding of the biology of these tumors, there have been no advancements in therapies for DMGs. Tumor heterogeneity and diffuse infiltration in inoperable brain regions make these tumors uniquely difficult to manage both surgically and pharmacologically. Therefore, there is an urgent need for the exploration of novel treatment regimens. Focused Ultrasound (FUS) is an emerging technology with significant clinical potentials. Sonodynamic therapy (SDT) is an up-and-coming treatment strategy aiming to non-invasively eliminate tumor cells by acting through compounds known as sonosensitizers, which render tumor cells sensitive to ultrasound energy. Recently, 5-Aminolevulinic acid (5-ALA), an FDA-approved molecule, has been proposed as a sono-sensitizing agent. 5-ALA mediated SDT prolonged survival in C6 rat glioma models by selective elimination of tumor cells upon sonication. Mechanistically, it is thought that 5-ALA uptake and metabolic conversion into Protoporphyrin IX (PpIX) occurs preferentially in tumor cells due to differential activity of enzymes involved in heme metabolism. Here, we investigated SDT in DMG cells treated with 5-ALA. PpIX fluorescence increased linearly up to 24 h upon 5-ALA treatment and accumulated significantly more (1.6-fold, p < 0.01) when compared to C6 cells. Consequently, FUS sonication of 5-ALA treated DMG cells at 250 kHz significantly (p < 0.05) decreased DMG cell viability compared to treatment with 5-ALA or FUS alone. Here, we show the first 5-ALA mediated sonodynamic effect in DMG cells, leading to enhanced cell death. Our findings provide a rationale for considering clinical investigation of 5-ALA mediated sonodynamic therapy in DMG.

scholarly journals Ibogaine Modifies GDNF, BDNF and NGF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits

2018 ◽  
Author(s):  
Soledad Marton ◽  
Bruno González ◽  
Sebastián Rodríguez ◽  
Ernesto Miquel ◽  
Laura Martínez Palma ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Acute Administration ◽  
Dependent Manner ◽  
Self Administration ◽  
Seeking Behavior ◽  
A Site ◽  
Dose Dependent

<p>Ibogaine is a psychedelic alkaloid which has been subject of intense scientific research due to its reported ability to attenuate drug-seeking behavior. Recent work suggested that ibogaine effects on alcohol self-administration in rats was related to the release of Glial Cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts soma of dopamine neurons. It is well known that neurotrophic factors (NFs) mediate the neuroadaptations induced in the mesocorticolimbic dopaminergic system by repeated exposure to drugs. Although previous reports have shown ibogaine´s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF, Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Thus, rats were i.p. treated with ibogaine 20 mg/kg (I<sub>20</sub>), 40 mg/kg (I<sub>40</sub>) or vehicle, and NFs expression was analyzed after 3 and 24 hours. Only at 24 h an increase of the expression for the three NFs were observed in a site and dose dependent manner. Results for GDNF showed that only I<sub>40</sub> selectively upregulated its expression in the VTA and SN. Both doses of ibogaine elicited a large increase in the expression of BDNF in the NAcc, SN and PFC, while a significant effect was found in the VTA only for I<sub>40</sub>. Finally, NGF was found to be upregulated in all regions after I<sub>40</sub>, while a selective upregulation was found in PFC and VTA for the I<sub>20</sub> treatment. An increase in the content of mature GDNF was observed in the VTA but no significant increase in the mature BDNF protein content was found in all the studied areas. Interestingly, an increase in the content of proBDNF was detected in the NAcc for both treatments. Further research is needed to understand the neurochemical bases of these changes, and to confirm their contribution to the anti-addictive properties of ibogaine. </p>

Thallium Induced Changes in Behavioral Patterns: Correlation With Altered Lipid Peroxidation and Lysosomal Enzyme Activity in Brain Regions of Male Rats

1985 ◽  
Vol 1 (1) ◽  
pp. 81-98 ◽  
Author(s):  
David R. Brown ◽  
Barbara G. Callahan ◽  
Mark A. Cleaves ◽  
Robert A. Schatz
Keyword(s):  
Lipid Peroxidation ◽  
Lysosomal Enzyme ◽  
Brain Regions ◽  
Male Rats ◽  
Patterns Of Behavior ◽  
Low Levels ◽  
Behavioral Sequelae ◽  
Human Poisoning ◽  
And Function ◽  
Induced Changes

The effects of exposures to low levels of heavy metals is a complex and serious problem. Thallium is a metal which produces behavioral sequelae in human poisoning and is potentially hazardous with low level exposures. A test battery is presented which utilizes biochemical and behavioral testing to assess the effects of low levels of thallium on central nervous system chemistry and function in rats. The doses of thallium used (4 and 8 mg/kg) produced no overt signs of behavioral toxicity but did produce dose-related increases in lipid peroxidation and activation of the lysosomal enzyme beta-galactosidase in selected brain regions. At these dose levels, thallium also selectively altered the patterns of behavior. The study suggests that the target regions of thallium in the brain include the cortex, the cerebellum and the brainstem. The dose-response relationships, found for certain pairs of behavioral acts, were correlated with biochemical changes in one or more brain regions.

A new targeted treatment for patients with a germline BRCA mutation: olaparib in pancreatic cancer

2020 ◽  
Vol 16 (33) ◽  
pp. 2691-2700
Author(s):  
Helena Verdaguer ◽  
Daniel Acosta ◽  
Teresa Macarulla
Keyword(s):  
Pancreatic Cancer ◽  
Poor Prognosis ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Phase Iii Clinical Trial ◽  
Novel Treatments ◽  
Phase Ii Clinical Trials ◽  
Germline Brca Mutation

Pancreatic cancer has a poor prognosis. Focused efforts in the development of novel treatments of this disease have led to the approval of new combinations. Improvements in knowledge of the biology of these tumors have been made, and it is now widely accepted that a proportion of patients have potentially targetable altered genes. One such gene is BRCA, which confers sensibility to PARP inhibitors. Olaparib, an oral PARP inhibitor, initially demonstrated activity in Phase II clinical trials including germline BRCA-mutated patients. This was confirmed in a Phase III clinical trial in pancreatic cancer patients with a germline BRCA mutation. After the results of this study, new scenarios have been evoked. We review the development of olaparib in pancreatic cancer.

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