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Molecular Neurobiology Oct 2022Evidence from clinical, preclinical, and post-mortem studies supports the inflammatory/immune hypothesis of schizophrenia pathogenesis. Less evident is the link between... (Review)
Review
Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review.
Evidence from clinical, preclinical, and post-mortem studies supports the inflammatory/immune hypothesis of schizophrenia pathogenesis. Less evident is the link between the inflammatory background and two well-recognized functional and structural findings of schizophrenia pathophysiology: the dopamine-glutamate aberrant interaction and the alteration of dendritic spines architecture, both believed to be the "quantal" elements of cortical-subcortical dysfunctional network. In this systematic review, we tried to capture the major findings linking inflammation, aberrant glutamate-dopamine interaction, and post-synaptic changes under a direct and inverse translational perspective, a paramount picture that at present is lacking. The inflammatory effects on dopaminergic function appear to be bidirectional: the inflammation influences dopamine release, and dopamine acts as a regulator of discrete inflammatory processes involved in schizophrenia such as dysregulated interleukin and kynurenine pathways. Furthermore, the link between inflammation and glutamate is strongly supported by clinical studies aimed at exploring overactive microglia in schizophrenia patients and maternal immune activation models, indicating impaired glutamate regulation and reduced N-methyl-D-aspartate receptor (NMDAR) function. In addition, an inflammatory/immune-induced alteration of post-synaptic density scaffold proteins, crucial for downstream NMDAR signaling and synaptic efficacy, has been demonstrated. According to these findings, a significant increase in plasma inflammatory markers has been found in schizophrenia patients compared to healthy controls, associated with reduced cortical integrity and functional connectivity, relevant to the cognitive deficit of schizophrenia. Finally, the link between altered inflammatory/immune responses raises relevant questions regarding potential new therapeutic strategies specifically for those forms of schizophrenia that are resistant to canonical antipsychotics or unresponsive to clozapine.
Topics: Antipsychotic Agents; Dopamine; Glutamic Acid; Humans; Inflammation; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 35963926
DOI: 10.1007/s12035-022-02976-3 -
Biomolecules Jun 2022Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical-subcortical connections. Antipsychotics are the... (Review)
Review
Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical-subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently available therapies. D-amino acids, acting as N-methyl-D-aspartate receptor (NMDAR) modulators, have emerged in the last few years as a potential augmentation strategy in those cases of schizophrenia that do not respond well to antipsychotics, a condition defined as treatment-resistant schizophrenia (TRS), affecting almost 30-40% of patients, and characterized by serious cognitive deficits and functional impairment. In the present systematic review, we address with a direct and reverse translational perspective the efficacy of D-amino acids, including D-serine, D-aspartate, and D-alanine, in poor responders. The impact of these molecules on the synaptic architecture is also considered in the light of dendritic spine changes reported in schizophrenia and antipsychotics' effect on postsynaptic density proteins. Moreover, we describe compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes. Finally, other drugs acting at NMDAR and proxy of D-amino acids function, such as D-cycloserine, sarcosine, and glycine, are considered in the light of the clinical burden of TRS, together with other emerging molecules.
Topics: Amino Acids; Antipsychotic Agents; Humans; Neurobiology; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenia, Treatment-Resistant
PubMed: 35883465
DOI: 10.3390/biom12070909 -
Current Reviews in Clinical and... 2024Parkinson's disease is the second most common neurological ailment. It is also known that it affects practically all other brain components, although only gradually....
BACKGROUND
Parkinson's disease is the second most common neurological ailment. It is also known that it affects practically all other brain components, although only gradually. Animal models are mostly used to test the efficacy of treatment against a specific enzyme and aid in creating a new drug dose.
OBJECTIVE
The purpose of this review is to highlight Parkinson's disease screening approaches, as well as the mechanism of action of each drug involved in Parkinson's disease development, and discuss the limitations of each model. In addition, it also sheds light on Parkinson's disease genetic models.
METHODS
The data for the publication was gathered from databases, such as PubMed, Bentham Science, Elsevier, Springer Nature, Wiley, and Research Gate, after a thorough examination of diverse research findings linked to Parkinson's disease and its screening models.
RESULTS
Each chemical or drug has a unique mechanism for causing disease, whether through the production of reactive oxygen species or the blockage of the dopamine receptor. Almost every disease symptom, whether physical or behavioral, is covered by each of the constructed models' unique set of indicators and symptoms.
CONCLUSION
Animal models are typically used to assess a medicine's activity against a specific enzyme and aid in the creation of a new drug dose. The process, restrictions, and mechanisms interfering with the screening, as well as the level of animal suffering, must all be thoroughly reviewed before any model for screening for Parkinson's disease can be implemented.
Topics: Animals; Disease Models, Animal; Parkinson Disease; Receptors, Dopamine; Humans
PubMed: 35796452
DOI: 10.2174/2772432817666220707101550 -
Pharmacology & Therapeutics Aug 2022Almost fifty years after its first introduction into clinical care, clozapine remains the only evidence-based pharmacological option for treatment-resistant... (Review)
Review
Clozapine's multiple cellular mechanisms: What do we know after more than fifty years? A systematic review and critical assessment of translational mechanisms relevant for innovative strategies in treatment-resistant schizophrenia.
Almost fifty years after its first introduction into clinical care, clozapine remains the only evidence-based pharmacological option for treatment-resistant schizophrenia (TRS), which affects approximately 30% of patients with schizophrenia. Despite the long-time experience with clozapine, the specific mechanism of action (MOA) responsible for its superior efficacy among antipsychotics is still elusive, both at the receptor and intracellular signaling level. This systematic review is aimed at critically assessing the role and specific relevance of clozapine's multimodal actions, dissecting those mechanisms that under a translational perspective could shed light on molecular targets worth to be considered for further innovative antipsychotic development. In vivo and in vitro preclinical findings, supported by innovative techniques and methods, together with pharmacogenomic and in vivo functional studies, point to multiple and possibly overlapping MOAs. To better explore this crucial issue, the specific affinity for 5-HTR, D1R, α, and muscarinic receptors, the relatively low occupancy at dopamine D2R, the interaction with receptor dimers, as well as the potential confounder effects resulting in biased ligand action, and lastly, the role of the moiety responsible for lipophilic and alkaline features of clozapine are highlighted. Finally, the role of transcription and protein changes at the synaptic level, and the possibility that clozapine can directly impact synaptic architecture are addressed. Although clozapine's exact MOAs that contribute to its unique efficacy and some of its severe adverse effects have not been fully understood, relevant information can be gleaned from recent mechanistic understandings that may help design much needed additional therapeutic strategies for TRS.
Topics: Antipsychotic Agents; Clozapine; Humans; Receptors, Dopamine D2; Schizophrenia; Schizophrenia, Treatment-Resistant
PubMed: 35764175
DOI: 10.1016/j.pharmthera.2022.108236 -
BMC Psychiatry May 2022Aripiprazole is a second-generation antipsychotic, efficacious in patients with schizophrenia during acute episodes. Due to its pharmacological profile, aripiprazole may...
BACKGROUND
Aripiprazole is a second-generation antipsychotic, efficacious in patients with schizophrenia during acute episodes. Due to its pharmacological profile, aripiprazole may be of interest in patients with specific clinical profiles who have not been studied extensively in randomised clinical trials.
OBJECTIVES
To capture experience with aripiprazole in everyday psychiatric practice using the Delphi method in order to inform decision-making on the use of aripiprazole for the treatment of patients with schizophrenia in clinical situations where robust evidence from clinical trials is lacking.
METHODS
The scope of the survey was defined as the management of schizophrenia in adults. A systematic literature review was performed to identify the different clinical situations in which aripiprazole has been studied, and to describe the level of clinical evidence. Clinical profiles to include in the Delphi survey were selected if there was a clear interest in terms of medical need but uncertainty over the efficacy of aripiprazole. For each clinical profile retained, five to seven specific statements were generated and included in a questionnaire. The final 41-item questionnaire was proposed to a panel of 406 French psychiatrists with experience in the treatment of schizophrenia. Panellists rated their level of agreement using a Likert scale. A second round of voting on eleven items was organised to clarify points for which a consensus was not obtained in the first round.
RESULTS
Five clinical profiles were identified in the literature review (persistent negative symptoms, pregnancy, cognitive dysfunction, addictive comorbidity and clozapine resistance). Sixty-two psychiatrists participated in the first round of the Delphi survey and 33 in the second round. A consensus was obtained for 11 out of 41 items in the first round and for 9/11 items in the second round. According to the panellists' clinical experience, aripiprazole can be used as maintenance treatment for pregnant women, is relevant to preserve cognitive function and can be considered an option in patients with a comorbid addictive disorder or with persistent negative symptoms.
CONCLUSION
These findings may help physicians in choosing relevant ways to use aripiprazole and highlight areas where more research is needed to widen the evidence base.
Topics: Adult; Aripiprazole; Delphi Technique; Dopamine; Dopamine Agonists; Female; Humans; Pregnancy; Schizophrenia
PubMed: 35643542
DOI: 10.1186/s12888-022-04008-9 -
Pharmacological Research Jul 2022Cannabis sativa is a recreational drug commonly consumed in Europe and is getting popularity for both recreational and therapeutic use. In some individuals, the use of... (Review)
Review
OBJECTIVE
Cannabis sativa is a recreational drug commonly consumed in Europe and is getting popularity for both recreational and therapeutic use. In some individuals, the use of cannabis leads to psychotic disorders. This systematic review summarizes the current evidence linking genetic polymorphisms and inter-individual susceptibility to psychosis induced by cannabis.
METHOD
Studies published from 2005 to 2020 were identified through Medline using PubMed, Web of Science and Scopus database and searches were conducted according to PRISMA guidelines. Initial search was performed with terms: "cannabis induced psychosis" AND "genetics".
RESULTS
From the initial group of 108 papers, 18 studies met our inclusion criteria. Many of the findings revealed associations with genetic polymorphisms modulations of genes involved directly (COMT, DRD2 and DAT) or indirectly (AKT1) to dopamine pathways. The most consistent finding was with COMT rs4680, where the presence of the Val allele was associated with a higher risk for cannabis-induced psychosis. This higher susceptibility was also reported for AKT1 (rs2494732) with the CC genotype. Of note, the only genome-wide association study identified a significant signal close to the cholinergic receptor muscarinic 3 represented by rs115455482 and rs74722579 predisposing to cannabis-induced hallucinations and remarkably no dopaminergic target was found.
CONCLUSION
Actual evidence supports the role of dopamine in cannabis induced psychosis. However, most of genetic polymorphism studies have as a starting point the pre-existing dopaminergic theoretical basis for psychosis. This alerts to the importance of more broad genetic studies. Integrate genetic results into biological systems may enhance our knowledge of cannabis induced psychosis and could help in the prevention and treatment of these patients.
Topics: Cannabis; Catechol O-Methyltransferase; Dopamine; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Marijuana Abuse; Polymorphism, Single Nucleotide; Psychotic Disorders
PubMed: 35588917
DOI: 10.1016/j.phrs.2022.106258 -
Environmental Science and Pollution... Jun 2022As well as a lead-related environmental factor, genetic factors could also corroborate important changes in intelligence quotient (IQ) through single-nucleotide...
As well as a lead-related environmental factor, genetic factors could also corroborate important changes in intelligence quotient (IQ) through single-nucleotide polymorphisms. Thus, a systematic review was carried out to evaluate the possible influence of polymorphism on blood Pb levels and IQ points in pediatric patients (0-19 years old). Following the PRISMA guideline, the studies were systematically collected on PubMed, Scopus, and Embase databases. Six genes (transferrin (TF); glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A); glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B); dopamine receptor D2/ankyrin repeat and kinase domain containing 1 ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1); aminolevulinate dehydratase (ALAD); vitamin D receptor (VDR)) were found in six selected articles. In these genes, 11 single-nucleotide polymorphisms were searched and six different types of variations (missense variant, intron variant, synonymous variant, stop, stop gained) were observed. Due to the few studies in the literature, there is no conclusive data to point out that there is a direct relationship between polymorphisms, Pb levels, and reduction of IQ points.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Young Adult; Genotype; Glutamates; Lead; N-Methylaspartate; Nucleotides; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases
PubMed: 35386084
DOI: 10.1007/s11356-022-19981-7 -
Progress in Neurobiology Jun 2022Alterations of the dopaminergic system may be important neurobiological correlates of vulnerability and transition to psychosis. We systematically reviewed the evidence... (Review)
Review
Alterations of the dopaminergic system may be important neurobiological correlates of vulnerability and transition to psychosis. We systematically reviewed the evidence for dopaminergic alterations demonstrated by in-vivo imaging studies in humans at increased risk of developing psychosis, covering clinical, genetic, and environmental high-risk groups. All 63 included studies utilized Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), or neuromelanin-sensitive Magnetic Resonance Imaging (NM-MRI) methods to collect data concerning the dopaminergic system during rest and/or following pharmacological, behavioural, or cognitive challenges. The current evidence highlights that 1) striatal dopamine D receptor availability is unaltered in all three high-risk groups compared with healthy individuals; 2) striatal dopamine synthesis capacity (sDSC) is increased in some clinical and genetic high-risk individuals relative to controls (e.g. people that meet clinical criteria for being at ultra-high risk of developing psychosis and individuals with 22q11.2 deletion syndrome), while sDSC is decreased in cannabis-using environmental high-risk individuals. It seems likely that all three high-risk groups can be stratified into multiple subgroups, with varying risks to develop psychosis, transition rates, and underlying neurobiology. The present results support the hypothesis that dopaminergic abnormalities occur before high-risk individuals develop psychosis.
Topics: Corpus Striatum; Dopamine; Humans; Positron-Emission Tomography; Psychotic Disorders; Tomography, Emission-Computed, Single-Photon
PubMed: 35351599
DOI: 10.1016/j.pneurobio.2022.102265 -
Neuroscience and Biobehavioral Reviews May 2022Once considered only scaffolding proteins at glutamatergic postsynaptic density (PSD), Homer1 proteins are increasingly emerging as multimodal adaptors that integrate... (Review)
Review
The Homer1 family of proteins at the crossroad of dopamine-glutamate signaling: An emerging molecular "Lego" in the pathophysiology of psychiatric disorders. A systematic review and translational insight.
Once considered only scaffolding proteins at glutamatergic postsynaptic density (PSD), Homer1 proteins are increasingly emerging as multimodal adaptors that integrate different signal transduction pathways within PSD, involved in motor and cognitive functions, with putative implications in psychiatric disorders. Regulation of type I metabotropic glutamate receptor trafficking, modulation of calcium signaling, tuning of long-term potentiation, organization of dendritic spines' growth, as well as meta- and homeostatic plasticity control are only a few of the multiple endocellular and synaptic functions that have been linked to Homer1. Findings from preclinical studies, as well as genetic studies conducted in humans, suggest that both constitutive (Homer1b/c) and inducible (Homer1a) isoforms of Homer1 play a role in the neurobiology of several psychiatric disorders, including psychosis, mood disorders, neurodevelopmental disorders, and addiction. On this background, Homer1 has been proposed as a putative novel target in psychopharmacological treatments. The aim of this review is to summarize and systematize the growing body of evidence on Homer proteins, highlighting the role of Homer1 in the pathophysiology and therapy of mental diseases.
Topics: Carrier Proteins; Dopamine; Glutamates; Homer Scaffolding Proteins; Humans; Mental Disorders; Signal Transduction
PubMed: 35248676
DOI: 10.1016/j.neubiorev.2022.104596 -
Cureus Dec 2021Attention-deficit hyperactivity disorder (ADHD) affects multiple cognitive domains, including impaired attention, hyperactivity, and increased impulsivity. According to... (Review)
Review
Attention-deficit hyperactivity disorder (ADHD) affects multiple cognitive domains, including impaired attention, hyperactivity, and increased impulsivity. According to the CDC, 9.4% of children between 2 and 17 years old have been diagnosed with ADHD. Neurotransmitters such as noradrenaline and dopamine have been suggested as crucial players in the pathophysiology of ADHD and are often targets of modern medication. Adenosine receptors types A1 and A2a in the brain are inhibited by caffeine: a stimulant known to augment attention by increasing cholinergic and dopaminergic transmission. The cognitive function of attention is also enhanced by the amino acid: L-theanine. The mechanism of action is that it behaves like a glutamate reuptake inhibitor while also acting in the hippocampus as a competitive low-affinity glutamate receptor antagonist. It's also shown to have a neuroprotective effect by its action on the gamma aminobutyric acid (GABA)-A receptors. Our systematic review investigates the literature and clinical trials on the cognitive-enhancing effects of caffeine and L-theanine.
PubMed: 35111479
DOI: 10.7759/cureus.20828