Perineuronal net density in schizophrenia: A systematic review of postmortem brain studies.

BACKGROUND: The onset of schizophrenia is concurrent with multiple key processes of brain development, such as the maturation of inhibitory networks. Some of these processes are proposed to depend on the development of perineuronal nets (PNNs), a specialized extracellular matrix structure that surrounds preferentially parvalbumin-containing GABAergic interneurons (PVIs). PNNs are fundamental to the postnatal experience-dependent maturation of inhibitory brain circuits. PNN abnormalities have been proposed as a core pathophysiological finding in SCZ, being linked to widespread consequences on circuit disruptions underlying SCZ symptoms. OBJECTIVE: Here, we systematically evaluate PNN density in postmortem brain studies of subjects with SCZ. METHODS: A systematic search in 3 online databases (PubMed, Embase, and Scopus) and qualitative review analysis of case-control studies reporting on PNN density in the postmortem brain of subjects with SCZ were performed. RESULTS: Results consisted of 7 studies that were included in the final analysis. The specific brain regions investigated in the studies varied, with most attention given to the dorsolateral prefrontal cortex (DLPFC; 3 studies) and amygdala (2 studies). Findings were mostly positive for reduced PNN density in SCZ, with 6 of the 7 studies reporting significant reductions and one reporting a tendency towards reduced PNN density. Overall, tissue processing methodologies were heterogeneous. CONCLUSIONS: Despite few studies, PNN density was consistently reduced in SCZ across different brain regions. These findings support evidence that implicates deficits in PNN density in the pathophysiology of SCZ. However, more studies, preferably using similar methodological approaches as well as replication of findings, are needed.

Cannabidiol in anxiety disorders: Current and future perspectives.

Anxiety disorders are highly prevalent psychiatric disorders, characterized by a chronic course and often accompanied by comorbid symptoms that impair functionality and decrease quality of life. Despite advances in basic and clinical research in our understanding of these disorders, currently available pharmacological options are associated with limited clinical benefits and side effects that frequently lead to treatment discontinuation. Importantly, a significant number of patients do not achieve remission and live with lifelong residual symptoms that limit daily functioning. Since the 1970s, basic and clinical research on cannabidiol (CBD), a non-psychotomimetic compound found in the Cannabis sativa plant, has indicated relevant anxiolytic effects, garnering attention for its therapeutic potential as an option in anxiety disorder treatment. This chapter aims to review the history of these studies on the anxiolytic effects of CBD within the current understanding of anxiety disorders. It highlights the most compelling current evidence supporting its anxiolytic effects and explores future perspectives for its clinical use in anxiety disorders.

Cannabidiol as an antipsychotic drug.

Cannabidiol (CBD) is a major phytocannabinoid in the Cannabis sativa plant. In contrast to Δ9-tetrahydrocannabinol (THC), CBD does not produce the typical psychotomimetic effects of the plant. In addition, CBD has attracted increased interest due to its potential therapeutic effects in various psychiatric disorders, including schizophrenia. Several studies have proposed that CBD has pharmacological properties similar to atypical antipsychotics. Despite accumulating evidence supporting the antipsychotic potential of CBD, the mechanisms of action in which this phytocannabinoid produces antipsychotic effects are still not fully elucidated. Here, we focused on the antipsychotic properties of CBD indicated by a series of preclinical and clinical studies and the evidence currently available about its possible mechanisms. Findings from preclinical studies suggest that CBD effects may depend on the animal model (pharmacological, neurodevelopmental, or genetic models for schizophrenia), dose, treatment schedule (acute vs. repeated) and route of administration (intraperitoneal vs local injection into specific brain regions). Clinical studies suggest a potential role for CBD in the treatment of psychotic disorders. However, future studies with more robust sample sizes are needed to confirm these positive findings. Overall, although more studies are needed, current evidence indicates that CBD may be a promising therapeutic option for the treatment of schizophrenia.

The excitatory-inhibitory balance as a target for the development of novel drugs to treat schizophrenia.

The intricate balance between excitation and inhibition (E/I) in the brain plays a crucial role in normative information processing. Dysfunctions in the E/I balance have been implicated in various psychiatric disorders, including schizophrenia (SCZ). In particular, abnormalities in GABAergic signaling, specifically in parvalbumin (PV)-containing interneurons, have been consistently observed in SCZ pathophysiology. PV interneuron function is vital for maintaining an ideal E/I balance, and alterations in PV interneuron-mediated inhibition contribute to circuit deficits observed in SCZ, including hippocampus hyperactivity and midbrain dopamine system overdrive. While current antipsychotic medications primarily target D2 dopamine receptors and are effective primarily in treating positive symptoms, novel therapeutic strategies aiming to restore the E/I balance could potentially mitigate not only positive symptoms but also negative symptoms and cognitive deficits. This could involve, for instance, increasing the inhibitory drive onto excitatory neurons or decreasing the putative enhanced pyramidal neuron activity due to functional loss of PV interneurons. Compounds targeting the glycine site at glutamate NMDA receptors and muscarinic acetylcholine receptors on PV interneurons that can increase PV interneuron drive, as well as drugs that increase the postsynaptic action of GABA, such as positive allosteric modulators of α5-GABA-A receptors, and decrease glutamatergic output, such as mGluR2/3 agonists, represent promising approaches. Preventive strategies aiming at E/I balance also represent a path to reduce the risk of transitioning to SCZ in high-risk individuals. Therefore, compounds with novel mechanisms targeting E/I balance provide optimism for more effective and tailored interventions in the management of SCZ.

Perineuronal nets as regulators of parvalbumin interneuron function: Factors implicated in their formation and degradation.

The brain extracellular matrix (ECM) has garnered increasing attention as a fundamental component of brain function in a predominantly "neuron-centric" paradigm. Particularly, the perineuronal nets (PNNs), a specialized net-like structure formed by ECM aggregates, play significant roles in brain development and physiology. PNNs enwrap synaptic junctions in various brain regions, precisely balancing new synaptic formation and long-term stabilization, and are highly dynamic entities that change in response to environmental stimuli, especially during the neurodevelopmental period. They are found mainly surrounding parvalbumin (PV)-expressing GABAergic interneurons, being proposed to promote PV interneuron maturation and protect them against oxidative stress and neurotoxic agents. This structural and functional proximity underscores the crucial role of PNNs in modulating PV interneuron function, which is critical for the excitatory/inhibitory balance and, consequently, higher-level behaviours. This review delves into the molecular underpinnings governing PNNs formation and degradation, elucidating their functional interactions with PV interneurons. In the broader physiological context and brain-related disorders, we also explore their intricate relationship with other molecules, such as reactive oxygen species and metalloproteinases, as well as glial cells. Additionally, we discuss potential therapeutic strategies for modulating PNNs in brain disorders.

Does the "Entourage Effect" in Cannabinoids Exist? A Narrative Scoping Review.

Background: The concept of an "entourage" effect in the cannabis and cannabinoids' field was first introduced in the late 1990s, during a period when most research on medical cannabinoids focused on the effects of isolated cannabinoids, such as cannabidiol and Δ9-tetrahydrocannabinol. Over the past decade, however, with the increased understanding of the endocannabinoid system, the discovery of other phytocannabinoids and their potential therapeutic uses, the term has gained widespread use in scientific reviews and marketing campaigns. Objective: Critically review the application of the term "entourage effect (EE)" in the literature and its endorsement by certain sectors of the cannabis market. Also, explore the perspectives for further interpretation and elaboration of the term based on current evidence, aiming to contribute to a more nuanced understanding of the concept and its implications for cannabinoid-based medicine. Methods: A comprehensive review of the literature was conducted to evaluate the current state of knowledge regarding the entourage effect. Relevant studies and scientific reviews were analyzed to assess the evidence of clinical efficacy and safety, as well as the regulation of cannabinoid-containing product production. Results: The EE is now recognized as a synergistic phenomenon in which multiple components of cannabis interact to modulate the therapeutic actions of the plant. However, the literature provides limited evidence to support it as a stable and predictable phenomenon. Hence, there is also limited evidence to support clinical efficacy, safety, and appropriate regulation for cannabinoid-containing products based on a "entourage" hypothesis. Conclusion: The EE has significant implications for the medical use of cannabinoid-containing products and their prescription. Nevertheless, a critical evaluation of the term's application is necessary. Further research and evidence are needed to establish the clinical efficacy, safety, and regulatory framework for these products. It's crucial that regulators, the pharmaceutical industry, the media, and health care providers exercise caution and avoid prematurely promoting the entourage effect hypothesis as a scientific proven phenomenon for cannabinoids and other cannabis-derived compound combinations.

Dermatites de contato causadas por aroeiras (Anacardiaceae) no estado de São Paulo, Brasil / Contact dermatitis caused by mastic (Anacardiaceae) in the state of São Paulo, Brazil

Contexto e objetivos: Aroeira é o nome popular de árvores da família Anacardiaceae, que inclui plantas sensibilizantes como a poison ivy norte-americana (Toxicodendron radicans), o cajueiro (Anacardium occidentale) e a mangueira (Mangifera indica). Este estudo procura caracterizar o conhecimento sobre as aroeiras e a frequência de manifestações clínicas em camponeses. Desenho e local: Foi realizado estudo retrospectivo e prospectivo com pacientes e acompanhantes residentes em ampla área rural de cerrado no Centro-Oeste paulista. Métodos: A frequência e a relação causal entre a exposição a aroeiras, comuns na região, e a dermatite eczematosa típica foi pesquisada. Para a avaliação, foi utilizado um questionário específico. Resultados: Todos os 39 entrevistados conheciam aroeiras (100%) e 17 deles (43,58%) relataram ter se aproximado ou descansado sob essas árvores. Mais da metade deles (56,41% ou 22 indivíduos) relataram dermatites que relacionaram às arvores. Os demais entrevistados não desenvolveram reações, mas conheciam pessoas que o fizeram (43,59%). Três pacientes, ou 7,69% da amostra, apresentavam lesões de padrão eczematoso, creditando-as ao contato com aroeiras-bravas (Lithraea molleoides). Discussão: Devido à alta frequência com que essas árvores são encontradas no campo (cerrado brasileiro) e aos dados obtidos, percebemos também uma alta frequência de sensibilização nas áreas rurais. Conclusões: É imperativo que as campanhas de orientação e alerta sejam desenvolvidas para aumentar a conscientização sobre riscos potenciais, de modo que o contato com essas árvores seja evitado, evitando condições alérgicas que podem ser tão extensas quanto graves.