Exploring ultrasonic communication in mice treated with Cannabis sativa oil: Audio data processing and correlation study with different behaviours.

Studying ultrasonic vocalizations (USVs) plays a crucial role in understanding animal communication, particularly in the field of ethology and neuropharmacology. Communication is associated with social behaviour; so, USVs study is a valid assay in behavioural readout and monitoring in this context. This paper delved into an investigation of ultrasonic communication in mice treated with Cannabis sativa oil (CS mice), which has been demonstrated having a prosocial effect on behaviour of mice, versus control mice (vehicle-treated, VH mice). To conduct this study, we created a dataset by recording audio-video files and annotating the duration of time that test mice spent engaging in social activities, along with categorizing the types of emitted USVs. The analysis encompassed the frequency of individual sounds as well as more complex sequences of consecutive syllables (patterns). The primary goal was to examine the extent and nature of diversity in ultrasonic communication patterns emitted by these two groups of mice. As a result, we observed statistically significant differences for each considered pattern length between the two groups of mice. Additionally, the study extended its research by considering specific behaviours, aiming to ascertain whether dissimilarities in ultrasonic communication between CS and VH mice are more pronounced or subtle within distinct behavioural contexts. Our findings suggest that while there is variation in USV communication between the two groups of mice, the degree of this diversity may vary depending on the specific behaviour being observed.

Cannabis Sativa Oil Promotes Social Interaction and Ultrasonic Communication by Acting on Oxytocin Pathway.

Objective: Cannabis sativa is the most used recreational drug worldwide. In recent years, there has been a growing interest in the potential therapeutic benefits of medicinal cannabis to treat a variety of psychiatric and neurological conditions. In particular, cannabidiol (CBD), a nonpsychoactive cannabis constituent, has been investigated for its potential prosocial effects on behavior, although the molecular mechanisms underlying this effect are still largely unknown. The aim of this study was to investigate the effect of a C. sativa oil CBD rich (CS oil) on social interaction and ultrasonic communication in mice. Study Design: Twenty-seven adult male mice (B6; 129P F2) were treated daily with vehicle or CS oil for 2 weeks. At Day 14, mice were tested for behavior (social interaction test and ultrasonic communication). Forty minutes before the behavioral tests, mice were exposed to intranasal treatment with vehicle or the oxytocin receptor antagonist, L-371,257. After behavioral tests, VH- and CS oil-treated mice were sacrificed, RNA was extracted from the hypothalamus and used for quantitative Real Time-PCR experiments. Results: We found that a 2-week treatment with the CS oil on mice exerted a prosocial effect associated with an increase in ultrasonic vocalizations. These effects were inhibited by pretreating mice with an oxytocin receptor antagonist. In addition, at the molecular level, we found that CS oil treatment caused a significant increase in oxytocin and a decrease in oxytocin receptor expression levels in the brain hypothalamus. Conclusion: Our results suggest that CS oil promotes social behavior by acting on oxytocin pathway.

Early Administration of the Phytocannabinoid Cannabidivarin Prevents the Neurobehavioral Abnormalities Associated with the Fmr1-KO Mouse Model of Fragile X Syndrome.

Phytocannabinoids, including the non-addictive cannabis component cannabidivarin (CBDV), have been reported to hold therapeutic potential in several neurodevelopmental disorders (NDDs). Nonetheless, the therapeutic value of phytocannabinoids for treating Fragile X syndrome (FXS), a major NDD, remains unexplored. Here, we characterized the neurobehavioral effects of CBDV at doses of 20 or 100 mg/kg in the Fmr1-knockout (Fmr1-KO) mouse model of FXS using two temporally different intraperitoneal regimens: subchronic 10-day delivery during adulthood (Study 1: rescue treatment) or chronic 5-week delivery at adolescence (Study 2: preventive treatment). Behavioral tests assessing FXS-like abnormalities included anxiety, locomotor, cognitive, social and sensory alterations. Expression of inflammatory and plasticity markers was investigated in the hippocampus and prefrontal cortex. When administered during adulthood (Study 1), the effects of CBDV were marginal, rescuing at the lower dose only the acoustic hyper-responsiveness of Fmr1-KO mice and at both doses their altered hippocampal expression of neurotrophins. When administered during adolescence (Study 2), CBDV at both doses prevented the cognitive, social and acoustic alterations of adult Fmr1-KO mice and modified the expression of several inflammatory brain markers in both wild-type littermates and mutants. These findings warrant the therapeutic potential of CBDV for preventing neurobehavioral alterations associated with FXS, highlighting the relevance of its early administration.

Extended performance analysis of deep-learning algorithms for mice vocalization segmentation.

Ultrasonic vocalizations (USVs) analysis represents a fundamental tool to study animal communication. It can be used to perform a behavioral investigation of mice for ethological studies and in the field of neuroscience and neuropharmacology. The USVs are usually recorded with a microphone sensitive to ultrasound frequencies and then processed by specific software, which help the operator to identify and characterize different families of calls. Recently, many automated systems have been proposed for automatically performing both the detection and the classification of the USVs. Of course, the USV segmentation represents the crucial step for the general framework, since the quality of the call processing strictly depends on how accurately the call itself has been previously detected. In this paper, we investigate the performance of three supervised deep learning methods for automated USV segmentation: an Auto-Encoder Neural Network (AE), a U-NET Neural Network (UNET) and a Recurrent Neural Network (RNN). The proposed models receive as input the spectrogram associated with the recorded audio track and return as output the regions in which the USV calls have been detected. To evaluate the performance of the models, we have built a dataset by recording several audio tracks and manually segmenting the corresponding USV spectrograms generated with the Avisoft software, producing in this way the ground-truth (GT) used for training. All three proposed architectures demonstrated precision and recall scores exceeding [Formula: see text], with UNET and AE achieving values above [Formula: see text], surpassing other state-of-the-art methods that were considered for comparison in this study. Additionally, the evaluation was extended to an external dataset, where UNET once again exhibited the highest performance. We suggest that our experimental results may represent a valuable benchmark for future works.

Mouse and rat ultrasonic vocalizations in neuroscience and neuropharmacology: State of the art and future applications.

Mice and rats emit ultrasonic vocalizations (USVs), which may express their arousal and emotional states, to communicate with each other. There is continued scientific effort to better understand the functions of USVs as a central element of the rodent behavioral repertoire. However, studying USVs is not only important because of their ethological relevance, but also because they are widely applied as a behavioral readout in various fields of biomedical research. In mice and rats, a large number of experimental models of brain disorders exist and studying the emission of USVs in these models can provide valuable information about the health status of the animals and the effectiveness of possible interventions, both environmental and pharmacological. This review (i) provides an updated overview of the contexts in which ultrasonic calling behaviour of mice and rats has particularly high translational value, and (ii) gives some examples of novel approaches and tools used for the analysis of USVs in mice and rats, combining qualitative and quantitative methods. The relevance of age and sex differences as well as the importance of longitudinal evaluations of calling and non-calling behaviour is also discussed. Finally, the importance of assessing the communicative impact of USVs in the receiver, that is, through playback studies, is highlighted.

The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology.

The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties in finding new drugs have led pharmacologists to review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists in psilocybin or lysergic acid diethylamide for the treatment of obsessive-compulsive disorder, of depression, or of post-traumatic stress disorder, although results are not always clear and definitive. In fact, the mechanisms of action of psychedelics are not yet fully understood and some molecular aspects have yet to be well defined. Thus, this review aims to summarize the ethnobotanical uses of the best-known psychedelic plants and the pharmacological mechanisms of the main active ingredients they contain. Furthermore, an up-to-date overview of structural and computational studies performed to evaluate the affinity and binding modes to biologically relevant receptors of ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, and lysergic acid diethylamide is presented. Finally, the most recent clinical studies evaluating the efficacy of psychedelic molecules in some psychiatric disorders are discussed and compared with drugs already used in therapy.

Long-term behavioral effects of prenatal stress in the Fmr1-knock-out mouse model for fragile X syndrome.

Fragile X syndrome (FXS) is a major neurodevelopmental disorder and the most common monogenic cause of autism spectrum disorder (ASD). FXS is caused by a mutation in the X-linked FMR1 gene leading to the absence of the FMRP protein, inducing several behavioral deficits, including motor, emotional, cognitive, and social abnormalities. Beside its clear genetic origins, FXS can be modulated by environmental factors, e.g., stress exposure: indeed the behavioral phenotype of FXS, as well as of ASD patients can be exacerbated by the repeated experience of stressful events, especially early in life. Here we investigated the long-term effects of prenatal exposure to unpredictable chronic stress on the behavioral phenotype of the Fmr1-knock-out (KO) mouse model for FXS and ASD. Mice were tested for FXS- and ASD-relevant behaviors first at adulthood (3 months) and then at aging (18 months), in order to assess the persistence and the potential time-related progression of the stress effects. Stress induced the selective emergence of behavioral deficits in Fmr1-KO mice that were evident in spatial memory only at aging. Stress also exerted several age-specific behavioral effects in mice of both genotypes: at adulthood it enhanced anxiety levels and reduced social interaction, while at aging it enhanced locomotor activity and reduced the complexity of ultrasonic calls. Our findings underline the relevance of gene-environment interactions in mouse models of neurodevelopmental syndromes and highlight the long-term behavioral impact of prenatal stress in laboratory mice.

Ultrasonic Vocalizations in Adult C57BL/6J Mice: The Role of Sex Differences and Repeated Testing.

Ultrasonic vocalizations (USVs) are a major tool for assessing social communication in laboratory mice during their entire lifespan. At adulthood, male mice preferentially emit USVs toward a female conspecific, while females mostly produce ultrasonic calls when facing an adult intruder of the same sex. Recent studies have developed several sophisticated tools to analyze adult mouse USVs, especially in males, because of the increasing relevance of adult communication for behavioral phenotyping of mouse models of autism spectrum disorder (ASD). Little attention has been instead devoted to adult female USVs and impact of sex differences on the quantitative and qualitative characteristics of mouse USVs. Most of the studies have also focused on a single testing session, often without concomitant assessment of other social behaviors (e.g., sniffing), so little is still known about the link between USVs and other aspects of social interaction and their stability/variations across multiple encounters. Here, we evaluated the USVs emitted by adult male and female mice during 3 repeated encounters with an unfamiliar female, with equal or different pre-testing isolation periods between sexes. We demonstrated clear sex differences in several USVs' characteristics and other social behaviors, and these were mostly stable across the encounters and independent of pre-testing isolation. The estrous cycle of the tested females exerted quantitative effects on their vocal and non-vocal behaviors, although it did not affect the qualitative composition of ultrasonic calls. Our findings obtained in B6 mice, i.e., the strain most widely used for engineering of transgenic mouse lines, contribute to provide new guidelines for assessing ultrasonic communication in male and female adult mice.

Autistic-like behavioral effects of prenatal stress in juvenile Fmr1 mice: the relevance of sex differences and gene-environment interactions.

Fragile X Syndrome (FXS) is the most common heritable form of mental retardation and monogenic cause of autism spectrum disorder (ASD). FXS is due to a mutation in the X-linked FMR1 gene and is characterized by motor, cognitive and social alterations, mostly overlapping with ASD behavioral phenotypes. The severity of these symptoms and their timing may be exacerbated and/or advanced by environmental adversity interacting with the genetic mutation. We therefore tested the effects of the prenatal exposure to unpredictable chronic stress on the behavioral phenotype of juveniles of both sexes in the Fmr1 knock-out (KO) mouse model of FXS. Mice underwent behavioral tests at 7-8 weeks of age, that is, when most of the relevant behavioral alterations are absent or mild in Fmr1-KOs. Stress induced the early appearance of deficits in spontaneous alternation in KO male mice, without exacerbating the behavioral phenotype of mutant females. In males stress also altered social interaction and communication, but mostly in WT mice, while in females it induced effects on locomotion and communication in mice of both genotypes. Our data therefore highlight the sex-dependent relevance of early environmental stressors to interact with genetic factors to influence the appearance of selected FXS- and ASD-like phenotypes.

Role of melatonin in autism spectrum disorders in a male murine transgenic model: Study in the prefrontal cortex.

Autism spectrum disorders (ASDs) are a group of clinically heterogeneous neurodevelopmental disorders sharing common features related to impaired social and communication abilities in addition to stereotyped behaviors. ASD patients present encephalic morphological, physiological, and biomolecular alterations with low levels of melatonin due to alterations in its pathways. Therefore, even if ASDs have traditionally been framed as behavioral disorders, several lines of evidence are accumulating that ASDs are characterized by certain anatomical and physiological abnormalities, including oxidative stress and inflammation in peripheral biomarkers, but likewise present in human brain tissue also characterized by alterations in synaptic remodeling and neuromodulation. Melatonin has also protective and antioxidant properties, so we can therefore hypothesize that alterations in melatonin's pathways may be one of the causes of the symptomatology of autism. The aim of the present study was to analyze the beneficial effect induced by melatonin administration and its possible mechanism of action in a transgenic mouse model of autism, immediately after weaning. The male mice were daily treated per os with melatonin (10 mg/Kg/day) or vehicle for 8 weeks starting from the sixth week of life. The antioxidant modulation, the GABAergic/glutamatergic impairment, and the synaptic remodeling in the prefrontal cortex have been evaluated. Social and repetitive behaviors were also evaluated. The behavioral results showed no statistical evidences, instead the immunohistochemical results indicated the ability of melatonin to promote the activity of antioxidant system, the GABAergic/glutamatergic equilibrium, and the synaptic remodeling. The results show that melatonin may be a possible adjuvant therapeutic strategy in ASDs.

Prosocial Effects of Nonpsychotropic Cannabis sativa in Mice.

Introduction:Cannabis sativa L. (C. sativa) is used since ancient times to produce fabrics, baskets, and cords. Later, different ethnic groups used to burn the leaves and flowers of psychotropic cultivars with high Δ9-tetrahydrocannabinol (D9-THC) levels, during the religious or propitiatory rites to alter the state of consciousness. To date, it is not known whether also nonpsychotropic cultivars of C. sativa were used during these rites, and whether these varieties could have an effect on human behavior. This study aimed to evaluate the behavioral effects of an extract of nonpsychotropic C. sativa (NP-CS) in mice. Materials and Methods: An extract of a nonpsychotropic cultivar of C. sativa dissolved in medium-chain triglyceride oil was used and the different phytochemical components were evaluated. The relative composition in terms of phytocannabinoid content was assessed by reverse phase high-performance liquid chromatography coupled to UV detection (RP-HPLC-UV), and the volatile components were analyzed by gas chromatography-mass spectrometry (GC-MS). In addition, the behavioral effect of NP-CS was assessed on a wild-type mouse model. The animals were treated for 14 days (oral gavage) and motility, anxiety, and social effects were assessed. Results: RP-HPLC-UV analysis demonstrated that D9-THC was present in lower concentration with respect to other cannabinoids, like cannabidiol. Furthermore, the GC-MS analysis revealed the presence of several terpenoids. Concerning in vivo studies, chronic treatment with NP-CS did not alter body weight, motility, and anxiety and increased social interaction. Conclusions: This study highlighted the prosocial effects of NP-CS.

Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder.

Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1-/- , CB1+/- , and CB1+/+ males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1-/- than CB1+/- mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains.

Protective Effects of Gynostemma pentaphyllum (var. Ginpent) against Lipopolysaccharide-Induced Inflammation and Motor Alteration in Mice.

Gynostemma pentaphyllum (var. Ginpent) (GP) is a variety of Cucurbit with anti-inflammatory and antioxidant effects in patients. In this manuscript, the main components present in the dry extract of GP have been identified using Ultra High Performance Liquid Chromatography quadrupole-time-of-flight mass spectrometry (UHPLC/Q-TOF-MS). In addition, the anti-inflammatory action of GP was evaluated in animal models with acute peripheral inflammation and motor alteration induced by lipopolysaccharide. The results showed that GP dry extract is rich in secondary metabolites with potential antioxidant and anti-inflammatory properties. We found that the treatment with GP induced a recovery of motor function measured with the rotarod test and pole test, and a reduction in inflammatory cytokines such as interleukin-1ß and interleukin-6 measured with the ELISA test. The data collected in this study on the effects of GP in in vivo models may help integrate the therapeutic strategies of inflammatory-based disorders.

Automatic classification of mice vocalizations using Machine Learning techniques and Convolutional Neural Networks.

Ultrasonic vocalizations (USVs) analysis is a well-recognized tool to investigate animal communication. It can be used for behavioral phenotyping of murine models of different disorders. The USVs are usually recorded with a microphone sensitive to ultrasound frequencies and they are analyzed by specific software. Different calls typologies exist, and each ultrasonic call can be manually classified, but the qualitative analysis is highly time-consuming. Considering this framework, in this work we proposed and evaluated a set of supervised learning methods for automatic USVs classification. This could represent a sustainable procedure to deeply analyze the ultrasonic communication, other than a standardized analysis. We used manually built datasets obtained by segmenting the USVs audio tracks analyzed with the Avisoft software, and then by labelling each of them into 10 representative classes. For the automatic classification task, we designed a Convolutional Neural Network that was trained receiving as input the spectrogram images associated to the segmented audio files. In addition, we also tested some other supervised learning algorithms, such as Support Vector Machine, Random Forest and Multilayer Perceptrons, exploiting informative numerical features extracted from the spectrograms. The performance showed how considering the whole time/frequency information of the spectrogram leads to significantly higher performance than considering a subset of numerical features. In the authors' opinion, the experimental results may represent a valuable benchmark for future work in this research field.

Ultrasonic vocalizations in mice: relevance for ethologic and neurodevelopmental disorders studies.

Mice use ultrasonic vocalizations (USVs) to communicate each other and to convey their emotional state. USVs have been greatly characterized in specific life phases and contexts, such as mother isolation-induced USVs for pups or female-induced USVs for male mice during courtship. USVs can be acquired by means of specific tools and later analyzed on the base of both quantitative and qualitative parameters. Indeed, different ultrasonic call categories exist and have already been defined. The understanding of different calls meaning is still missing, and it will represent an essential step forward in the field of USVs. They have long been studied in the ethological context, but recently they emerged as a precious instrument to study pathologies characterized by deficits in communication, in particular neurodevelopmental disorders (NDDs), such as autism spectrum disorders. This review covers the topics of USVs characteristics in mice, contexts for USVs emission and factors that modulate their expression. A particular focus will be devoted to mouse USVs in the context of NDDs. Indeed, several NDDs murine models exist and an intense study of USVs is currently in progress, with the aim of both performing an early diagnosis and to find a pharmacological/behavioral intervention to improve patients' quality of life.

Brain Structural and Functional Alterations in Mice Prenatally Exposed to LPS Are Only Partially Rescued by Anti-Inflammatory Treatment.

Aberrant immune activity during neurodevelopment could participate in the generation of neurological dysfunctions characteristic of several neurodevelopmental disorders (NDDs). Numerous epidemiological studies have shown a link between maternal infections and NDDs risk; animal models of maternal immune activation (MIA) have confirmed this association. Activation of maternal immune system during pregnancy induces behavioral and functional alterations in offspring but the biological mechanisms at the basis of these effects are still poorly understood. In this study, we investigated the effects of prenatal lipopolysaccharide (LPS) exposure in peripheral and central inflammation, cortical cytoarchitecture and behavior of offspring (LPS-mice). LPS-mice reported a significant increase in interleukin-1ß (IL-1ß) serum level, glial fibrillary acidic protein (GFAP)- and ionized calcium-binding adapter molecule 1 (Iba1)-positive cells in the cortex. Furthermore, cytoarchitecture analysis in specific brain areas, showed aberrant alterations in minicolumns' organization in LPS-mice adult brain. In addition, we demonstrated that LPS-mice presented behavioral alterations throughout life. In order to better understand biological mechanisms whereby LPS induced these alterations, dams were treated with meloxicam. We demonstrated for the first time that exposure to LPS throughout pregnancy induces structural permanent alterations in offspring brain. LPS-mice also present severe behavioral impairments. Preventive treatment with meloxicam reduced inflammation in offspring but did not rescue them from structural and behavioral alterations.

Specific profile of ultrasonic communication in a mouse model of neurodevelopmental disorders.

Mice emit ultrasonic vocalizations (USVs) in different social conditions: pups maternal separation, juveniles play, adults mating and social investigation. The USVs measurement has become an important instrument for behavioural phenotyping in neurodevelopmental disorders (NDDs). Recently, we have demonstrated that the deletion of the NFκB1 gene, which encodes the p50 NF-κB subunit, causes NDDs phenotype in mice. In this study, we investigated the ultrasonic communication and the effects of an early social enrichment in mice lacking the NF-κB p50 subunit (p50 KO). In particular, USVs of wild-type (WT), p50 KO and KO exposed to early social enrichment (KO enriched) were recorded using an ultrasound sensitive microphone and analysed by Avisoft software. USVs analysis showed that p50 KO pups emit more and longer vocalizations compared to WT pups. On the contrary, in adulthood, p50 KO mice emit less USVs than WT mice. We also found significant qualitative differences in p50 KO mice USVs compared to WT mice; the changes specifically involved two USVs categories. Early social enrichment had no effect on USVs number, duration and type in p50 KO mice. Together, these data revealed social communication alterations in a mouse model of NDDs; these deficits were not recovered by early social enrichment, strengthening the fact that genetic background prevails on environmental enrichment.

Gamma-oryzanol Prevents LPS-induced Brain Inflammation and Cognitive Impairment in Adult Mice.

BACKGROUND: Rice (Oryza sativa L.) is the main food source for more than half of humankind. Rice is rich in phytochemicals and antioxidants with several biological activities; among these compounds, the presence of γ-oryzanol is noteworthy. The present study aims to explore the effects of γ-oryzanol on cognitive performance in a mouse model of neuroinflammation and cognitive alterations. METHODS: Mice received 100 mg/kg γ-oryzanol (ORY) or vehicle once daily for 21 consecutive days and were then exposed to an inflammatory stimulus elicited by lipopolysaccharide (LPS). A novel object recognition test and mRNA expression of antioxidant and neuroinflammatory markers in the hippocampus were evaluated. RESULTS: ORY treatment was able to improve cognitive performance during the neuroinflammatory response. Furthermore, phase II antioxidant enzymes such as heme oxygenase-1 (HO-1) and NADPH-dehydrogenase-quinone-1 (NQO1) were upregulated in the hippocampi of ORY and ORY+LPS mice. Lastly, γ-oryzanol showed a strong anti-inflammatory action by downregulating inflammatory genes after LPS treatment. CONCLUSION: These results suggest that chronic consumption of γ-oryzanol can revert the LPS-induced cognitive and memory impairments by promoting hippocampal antioxidant and anti-inflammatory molecular responses.

Zeolite Clinoptilolite: Therapeutic Virtues of an Ancient Mineral.

Zeolites are porous minerals with high absorbency and ion-exchange capacity. Their molecular structure is a dense network of AlO4 and SiO4 that generates cavities where water and other polar molecules or ions are inserted/exchanged. Even though there are several synthetic or natural occurring species of zeolites, the most widespread and studied is the naturally occurring zeolite clinoptilolite (ZC). ZC is an excellent detoxifying, antioxidant and anti-inflammatory agent. As a result, it is been used in many industrial applications ranging from environmental remediation to oral applications/supplementation in vivo in humans as food supplements or medical devices. Moreover, the modification as micronization of ZC (M-ZC) or tribomechanically activated zeolite clinoptilolite (TMAZ) or furthermore as double tribomechanically activated zeolite clinoptilolite (PMA-ZC) allows improving its benefits in preclinical and clinical models. Despite its extensive use, many underlying action mechanisms of ZC in its natural or modified forms are still unclear, especially in humans. The main aim of this review is to shed light on the geochemical aspects and therapeutic potentials of ZC with a vision of endorsing further preclinical and clinical research on zeolites, in specific on the ZC and its modified forms as a potential agent for promoting human brain health and overall well-being.

Cannabimimetic plants: are they new cannabinoidergic modulators?

MAIN CONCLUSION: Phytochemicals and secondary metabolites able to interact with the endocannabinoid system (Cannabimimetics) have been recently described in a broad range of plants and fruits. These findings can open new alternative avenues to explore for the development of novel therapeutic compounds. The cannabinoids regulate many physiological and pathological functions in both animals and plants. Cannabis sativa is the main plant that produces phytocannabinoids inside resins capable to defend the plant from the aggression of parasites and herbivores. Animals produce anandamide and 2-arachidonoyl glycerol, which thanks to binding with main receptors such as type-1 cannabinoid receptor (CB1R) and the type-2 cannabinoid receptor (CB2R) are involved in inflammation processes and several brain functions. Endogenous cannabinoids, enzymes for synthesis and degradation of cannabinoids, and CB1R and CB2R constitute the endocannabinoid system (ECS). Other plants can produce cannabinoid-like molecules such as perrottetinene extracted from Radula perrottetii, or anandamide and 2-arachidonoyl glycerol extracted from some bryophytes. Moreover, several other secondary metabolites can also interact with the ECS of animals and take the name of cannabimimetics. These phytoextracts not derived from Cannabis sativa can act as receptor agonists or antagonist, or enzyme inhibitors of ECS and can be involved in the inflammation, oxidative stress, cancer, and neuroprotection. Finally, given the evolutionary heterogeneity of the cannabimimetic plants, some authors speculated on the fascinating thesis of the evolutionary convergence between plants and animals regarding biological functions of ECS. The review aims to provide a critical and complete assessment of the botanical, chemical and therapeutic aspects of cannabimimetic plants to evaluate their spread in the world and medicinal potentiality.