Motor behavior induced by bergamot essential oil in experimental tasks is differentially modulated by pretreatment with metabotropic glutamate receptor 2/3 or 5 antagonists.

Bergamot essential oil shows anxiolytic-relaxant effects devoid of sedative action and motor impairment typical of benzodiazepines. Considering the potential for clinical of these effects, it is important to understand the underlying mechanisms of the phytocomplex. Modulation of glutamate group I and II metabotropic receptors is involved in stress and anxiety disorders, in cognition and emotions and increases locomotor activity and wakefulness. Interestingly, early data indicate that bergamot essential oil modulates glutamatergic transmission in specific manifestations of the central nervous system. The aim of this work is to investigate if selective antagonists of metabotropic glutamate 2/3 and 5 receptors affect behavioral parameters modulated by the phytocomplex. Male Wistar rats were used to measure behavioral parameters to correlate anxiety and motor activity using elevated plus maze (EPM), open field (OF), and rotarod tasks. Bergamot essential oil increases in EPM the time spent in open/closed arms and reduces total number of entries. The essential oil also increases immobility in EPM and OF and not affect motor coordination in rotarod. Pretreatment with the metabotropic glutamate antagonists does not affect the time spent in open/close arms, however, differently affects motor behavior measured after administration of phytocomplex. Particularly, glutamate 2/3 antagonist reverts immobility and glutamate 5 antagonist potentiates this parameter induced by the phytocomplex. Our data show that modulation of both metabotropic glutamate receptors is likely involved in some of behavioral effects of bergamot essential oil.

Efficacy of Essential Oils in Relieving Cancer Pain: A Systematic Review and Meta-Analysis.

Over 80% of patients affected by cancer develops cancer-related pain, one of the most feared consequences because of its intractable nature, particularly in the terminal stage of the disease. Recent evidence-based recommendations on integrative medicine for the management of cancer pain underline the role of natural products. The present systematic review and meta-analysis aims at appraising for the first time the efficacy of aromatherapy in cancer pain in clinical studies with different design according to the most updated Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 recommendations. The search retrieves 1002 total records. Twelve studies are included and six are eligible for meta-analysis. The present study demonstrates significant efficacy of the use of essential oils in the reduction of the intensity of pain associated with cancer (p < 0.00001), highlighting the need for earlier, more homogeneous, and appropriately designed clinical trials. Good certainty body of evidence is needed for effective and safe management of cancer-related pain using essential oils by establishment of a step-by-step preclinical-to-clinical pathway to provide a rational basis for clinical use in integrative oncology. PROSPERO registration: CRD42023393182.

Translational Value of the Transdermal Administration of Bergamot Essential Oil and of Its Fractions.

The essential oil of bergamot (BEO) has consistently proven antinociceptive and antiallodynic properties. Accordingly, the analgesic efficacy of the decolored essential oil (DEC), with higher levels of limonene, and the deterpenated (DET) fraction, with higher levels of linalool and linalyl acetate, was investigated using a formalin test after inhalation. The present study was aimed at characterizing the effects of BEO, its components with the highest pharmacological activity (represented by linalool, limonene, and linalyl acetate), and its DEC and DET fractions on the formalin test after transdermal administration relevant to clinical translation through topical application. To this aim, the schedule of intervention involved administration immediately after formalin injection or as a 5 min pretreatment followed by washout in ddY-strain mice. This study demonstrates, for the first time, the significant analgesic effect of all three constituents in the first and second phases, accounting for the efficacy of the essential oil in the formalin test. While all fractions revealed equal activity toward the phytocomplex in the early phase, the reduction in time of licking/biting during the late phase was more markedly induced by DEC. Moreover, pretreatment with BEO and its fractions followed by washout did not produce a significant reduction in licking/biting time in both phases of formalin-induced nociceptive response.

Antispasmodic Effect of Bergamot Essential Oil on Rat Isolated Gut Tissues.

Preclinical data indicate that bergamot essential oil (BEO) can modulate the synaptic functions within the central nervous system (CNS). Particularly, several data shows that essential oil is endowed with reproducible analgesic and anxiolytic effects that may derived from the ability to modulate the excitatory and inhibitory neurotransmission in the CNS. Although there are differences in the functional complexity of the enteric nervous system (ENS), it is likely that the phytocomplex has biological properties in gut superimposable to those showed in the CNS. Accordingly, the aim of this study was to investigate ex-vivo the effect of bergamot essential oil and its main constituents on the contractile activity of rat isolated colon, jejunum and ileum induced by different muscle stimulants such as acetylcholine (10-6 M) and potassium chloride (80 mM). Our present data demonstrate that BEO inhibits cholinergically- and non cholinergically-mediated contractions in rat isolated gut and that linalool is the most active component. These results suggest that the phytocomplex might be useful in the treatment of spastic disorders in ENS mainly characterized by the presence of pain; incidentally, irritable bowel syndrome (IBS) is a painful condition in which a role for neurotransmitter dysfunction has been envisaged. More investigation is required for clinical translation of the present data.

Development and Translation of NanoBEO, a Nanotechnology-Based Delivery System of Bergamot Essential Oil Deprived of Furocumarins, in the Control of Agitation in Severe Dementia.

Dementia is one of the most common causes of disability worldwide characterized by memory loss, cognitive impairment, and behavioral and psychological symptoms (BPSD), including agitation. Treatment of the latter consists of the off-label use of harmful atypical antipsychotics, though a significant reduction is afforded by pain control. The use of an essential oil endowed with analgesic properties and devoid of toxicity would represent an important option for the management of agitation in dementia. Therefore, the aim of this study was to engineer a nanotechnology delivery system based on solid lipid nanoparticles loaded with bergamot essential oil (BEO) and devised in the pharmaceutical form of an odorless cream (NanoBEO) to confirm its analgesic efficacy for further development and application to control agitation in dementia. BEO has proven strong antinociceptive and anti-allodynic properties and, in its bergapten-free form, it is completely devoid of phototoxicity. NanoBEO has been studied in vivo confirming the previously reported analgesic activity of BEO to which is now added its anti-itching properties. Due to the nanotechnology delivery system, the stability of titrated BEO components is guaranteed. Finally, the latter invention, currently under patent consideration, is smell-devoid allowing efficacy and safety to be established in double-blind clinical trials; until now the latter studies have been impeded in aromatherapy by the strong odor of essential oils. A clinical trial NCT04321889 has been designed to provide information about the efficacy and safety of NanoBEO on agitation and pain in patients suffering from severe dementia.

Efficacy of Essential Oils in Pain: A Systematic Review and Meta-Analysis of Preclinical Evidence.

Background: The demand for essential oils (EOs) has been steadily growing over the years. This is mirrored by a substantial increase in research concerned with EOs also in the field of inflammatory and neuropathic pain. The purpose of this present systematic review and meta-analysis is to investigate the preclinical evidence in favor of the working hypothesis of the analgesic properties of EOs, elucidating whether there is a consistent rational basis for translation into clinical settings. Methods: A literature search has been conducted on databases relevant for medical scientific literature, i.e., PubMed/MEDLINE, Scopus, and Web of Science from database inception until November 2, 2020, following the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) criteria for systematic reviews and meta-analyses. Results: The search was conducted in order to answer the following PICOS (participants/population, interventions, comparisons, outcomes, and study design) question: are EOs efficacious in reducing acute nociceptive pain and/or neuropathic pain in mice experimental models? The search retrieved 2,491 records, leaving 954 studies to screen after the removal of duplicates. The title and abstract of all 954 studies were screened, which left 127 records to evaluate in full text. Of these, 30 articles were eligible for inclusion. Conclusion: Most studies (27) assessed the analgesic properties of EOs on acute nociceptive pain models, e.g. the acetic acid writhings test, the formalin test, and the hot plate test. Unfortunately, efficacy in neuropathic pain models, which are a more suitable model for human conditions of chronic pain, had fewer results (only three studies). Moreover, some methodologies raised concerns in terms of the risk of bias. Therefore, EOs with proven efficacy in both types of pain were corroborated by methodologically consistent studies, like the EO of bergamot, which should be studied in clinical trials to enhance the translational impact of preclinical modeling on clinical pain research.

Pattern of treatment of behavioural and psychological symptoms of dementia and pain: evidence on pharmacoutilization from a large real-world sample and from a centre for cognitive disturbances and dementia.

PURPOSE: Data concerning the number of diagnoses and of the drugs prescribed to patients affected by dementia are still scarce. Here we test whether or not (1) prescription of symptomatic drugs against Alzheimer's disease (AD) may approximate the number of patients affected by dementia in Italy and (2) adherence to this treatment affects the pattern of prescription of drugs (i.e. antipsychotics and antidepressants) for behavioural and psychological symptoms of dementia (BPSD) and the previously reported limited prescription of analgesics. METHODS: This retrospective observational study concerns 84,235 subjects older than 60 years and registered in the provincial prescription database of the health district of Cosenza accounting for a population of 298,000 inhabitants. The prescribing pattern of antipsychotics, antidepressants, and analgesics has been investigated in patients receiving concurrent prescriptions of acetylcholinesterase inhibitors (AChEI) and/or memantine. Data from a single centre for cognitive disturbances and dementia (CDCD) in the same health district were used to explore at which stage dementia was diagnosed. The study was approved by Calabria Region Ethical Committee no. 31/2017 and registered on October 31, 2017. RESULTS: The data show that 859 patients are treated with AChEI and/or memantine; 420 patients (48.89%) receive at least 80% of the recommended medications. CDCD data indicate a delay in dementia diagnosis, which often was made when the patients were moderately to severely demented (Mini Mental State Examination, MMSE ≤ 20). Adherence did not influence prescription of most of the drugs explored, but use of non-steroidal anti-inflammatory drugs was higher in non-adherent patients. Antipsychotics and antidepressants are frequently used (20.61-20.71% and 42.37-51.43%, respectively), and this, at least in part, might stem from the observed under-treatment of chronic pain (opioids are prescribed in the 4.76% and 12.46% of adherent and non-adherent patients and gabapentin and pregabalin are used in the 4.29% and 4.07% of adherent and non-adherent patients respectively), resulting in more frequent BPSD. 16.43% of patients receive antipsychotics for longer than 6-12 weeks. CONCLUSION: This 2-year period study, including a wide cohort of community demented patients, shows that dementia is diagnosed late and that prevalence of BPSD prescriptions is high and not impacted by adherence to anti-dementia drugs. The rate of prescription of potentially harmful antipsychotics and antidepressants appears to be high though whether the concomitantly observed limited prescription of analgesics might be a contributing factor needs to be further investigated. Our data support the development of strategies to improve the management of BPSD.

Natural Products: Evidence for Neuroprotection to Be Exploited in Glaucoma.

Glaucoma, a leading cause of irreversible blindness worldwide, is an optic neuropathy characterized by the progressive death of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is recognized as the main risk factor. Despite effective IOP-lowering therapies, the disease progresses in a significant number of patients. Therefore, alternative IOP-independent strategies aiming at halting or delaying RGC degeneration is the current therapeutic challenge for glaucoma management. Here, we review the literature on the neuroprotective activities, and the underlying mechanisms, of natural compounds and dietary supplements in experimental and clinical glaucoma.

Impact of nutraceuticals on glaucoma: A systematic review.

BACKGROUND: glaucoma is a remarkable social issue being the leading cause of irreversible blindness worldwide. It is a progressive neuropathy characterized by the death of the retinal ganglion cells, of which the most important risk factor is represented by the increase of intraocular pressure (IOP). The role of nutraceutical supplementations with anti-oxidant activity has been extensively tested in preclinical models of glaucoma. The clinical efficacy of nutraceuticals in glaucoma is still controversial. OBJECTIVES: the aim of this systematic review is to assess the efficacy of nutraceuticals with anti-oxidant activity in glaucoma through the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) rigorous criteria. DATA SOURCES: the literature search has been performed on the electronic databases currently recognized of most relevance for medical scientific literature, i.e. PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials (CENTRAL) with access to EMBASE, ClinicalTrials.gov and Scopus. The date of last search is April 8th, 2020. Study eligibility criteria, participants, and interventions: prospective randomized clinical trials assessing the effects of nutraceuticals and anti-oxidants on IOP and/or visual field in patients with glaucoma. The eligible papers must be published in English and available in full text. STUDY APPRAISAL AND SYNTHESIS METHODS: the evaluation of the eligibility of the studies has been carried out independently by two authors. The selection process has followed the PRISMA flow diagram, assessing the quality of the body of evidence and the risk of bias. RESULTS: the search of literature has retrieved 1615 papers and 2 clinical trials with results, among which only 6 are eligible for inclusion in the present systematic review to address the preset participants, interventions, comparisons, outcomes and study design (PICOS) "are the nutraceuticals effective in glaucoma?". In 5 out of 6 studies the nutraceutical supplementation is effective in providing additional decrease of IOP to current usual therapy, without the occurrence of side effects. However, all the studies present high heterogeneity and some concerns in terms of risk of bias, apart from one trial for which the risk of bias is low. CONCLUSIONS: the evidence of effectiveness of nutraceutical formulations is still uncertain and inconclusive. Therefore, large double-blind randomized clinical trials with adequate design, methodology and statistical power are needed to support the use of nutraceuticals in glaucoma.

Effects of caloric restriction on retinal aging and neurodegeneration.

Glaucoma is the most common neurodegenerative cause of irreversible blindness worldwide. Restricted caloric regimens are an attractive approach for delaying the progression of neurodegenerative diseases. Here we review the current literature on the effects of caloric restriction on retinal neurons, under physiological and pathological conditions. We focused on autophagy as one of the mechanisms modulated by restricted caloric regimens and involved in the death of retinal ganglion cells (RGCs) over the course of glaucoma.

Pharmacokinetic Interactions between Herbal Medicines and Drugs: Their Mechanisms and Clinical Relevance.

The therapeutic efficacy of a drug or its unexpected unwanted side effects may depend on the concurrent use of a medicinal plant. In particular, constituents in the medicinal plant extracts may influence drug bioavailability, metabolism and half-life, leading to drug toxicity or failure to obtain a therapeutic response. This narrative review focuses on clinical studies improving knowledge on the ability of selected herbal medicines to influence the pharmacokinetics of co-administered drugs. Moreover, in vitro studies are useful to anticipate potential herbal medicine-drug interactions. In particular, they help to elucidate the cellular target (metabolic or transporter protein) and the mechanism (induction or inhibition) by which a single constituent of the herbal medicine acts. The authors highlight the difficulties in predicting herbal-drug interactions from in vitro data where high concentrations of extracts or their constituents are used and pharmacokinetics are missed. Moreover, the difficulty to compare results from human studies where different kinds of herbal extracts are used is discussed. The herbal medicines discussed are among the best sellers and they are reported in the "Herbal Medicines for Human Use" section of the European Medicinal Agency (EMA).

Inhibition of Neuromuscular Contractions of Human and Rat Colon by Bergamot Essential Oil and Linalool: Evidence to Support a Therapeutic Action.

Bergamot essential oil (BEO) added to food and drink promotes a citrus flavour. Folklore suggests benefits on gastrointestinal functions but with little supporting evidence. BEO and major constituents (linalool, limonene, linalyl acetate) were therefore examined for any ability to influence neuromuscular contractions of human and rat colon. Circular muscle strips (macroscopically-normal human colon obtained following ethical approval at cancer surgery; Sprague-Dawley rats) were suspended in baths (Krebs solution; 37 °C; 5% CO2 in O2) for measurement of neuronally-mediated contractions (prevented by tetrodotoxin or atropine) evoked by electrical field stimulation (5 Hz, 0.5 ms pulse width, 10s/minute, maximally-effective voltage), or contractions evoked by KCl (submaximally-effective concentrations). BEO and each constituent concentration dependently inhibited neuronally-mediated and KCl-induced contractions. In human: apparent pIC50 for BEO (volume/volume Krebs), respectively, 3.8 ± 0.3 and 4.4 ± 0.3; Imax 55.8% ± 4.2% and 37.5% ± 4.2%. For the constituents, the rank order of potency differed in human (linalool > limonene >> linalyl-acetate) and rat colon (linalyl-acetate > limonene = linalool), but rank order of efficacy was similar (linalool >> (BEO) = linalyl-acetate >> limonene). Thus, linalool had high efficacy but greater potency in human colon (Imax 76.8% ± 6.9%; pIC50 6.7 ± 0.2; n = 4) compared with rat colon (Imax 75.3% ± 1.9%; pIC50 5.8 ± 0.1; n = 4). The ability of BEO and linalool to inhibit human colon neuromuscular contractility provides a mechanism for use as complementary treatments of intestinal disorders.

Effects of Aging on Formalin-Induced Pain Behavior and Analgesic Activity of Gabapentin in C57BL/6 Mice.

Improved living conditions have induced an increase of lifespan often accompanied by comorbidities, responsible for pain, and by cognitive impairment and dementia, impairing communication capabilities. In most cases, the elderly do not receive pain relief because of underdiagnosis and of aging-induced changes of systems affecting nociceptive response. Unrelieved pain is involved in the development of behavioral symptoms, as agitation, representing a difficult challenge in this fragile population. Aged C57BL/6 mice and amyloid precursor protein (APP) mice display behavioral disturbances that mimic behavioral and psychological symptoms of dementia (BPSD). Therefore, this original study focuses on the influence of aging on nociception to provide insight into the occurrence of BPSD. We have investigated how aging can affect nociception after formalin administration and gabapentin effect in C57BL/6 mice, since it represents one of the treatments of choice for chronic neuropathic pain. Based on our results, changes of nociceptive behavior in response to an algogen stimulus occur during aging. Formalin-induced behavioral pattern in older C57BL/6 mice presents a temporal shift and an increase in the peak amplitudes. Our data show that the effectiveness of gabapentin is influenced by the age of the animal; though preliminary, the latter provide evidence upon which formalin test induced long-lasting mechanical allodynia might be a reliable as rapid and viable persistent pain model. The disclosed differences in effectiveness of gabapentin according to age can form the rational basis to deepen the study of pain treatment in the elderly.

Role of 5-HT1A Receptor in the Anxiolytic-Relaxant Effects of Bergamot Essential Oil in Rodent.

The essential oil obtained by the fresh fruit of Citrus bergamia Risso et Poiteau is used worldwide in aromatherapy to reduce pain, facilitate sleep induction, and/or minimize the effects of stress-induced anxiety. Preclinical pharmacological data demonstrate that bergamot essential oil (BEO) modulates specific neurotransmissions and shows an anxiolytic-relaxant effect not superimposable to that of the benzodiazepine diazepam, suggesting that neurotransmissions, other than GABAergic, could be involved. Several studies on essential oils indicate a role for serotonergic (5-HT) neurotransmission in anxiety. Interestingly, among serotonergic receptors, the 5-HT1A subtype seems to play a key role in the control of anxiety. Here, we report that modulation of the 5-HT1A receptor by selective agonist ((±)8-OH-DPAT) or antagonist (WAY-100635) may influence some of the anxiolytic-relaxant effects of BEO in Open Field and Elevated Plus Maze tests.

The Role of Autophagy in Glaucomatous Optic Neuropathy.

Autophagy is a conserved lysosomal-dependent pathway responsible for the degradation of cytoplasmic macromolecules. Based on the mechanism of cargo delivery to lysosomes, mammalian cells can undergo micro, macro, and chaperone-mediated autophagy. Other than physiological turnover of proteins and organelles, autophagy regulates cellular adaptation to different metabolic states and stressful conditions by allowing cellular survival or, when overactivated, participating to cell death. Due to their structure and function, neurons are highly dependent on autophagy efficiency and dysfunction of the pathway has been associated with neurodegenerative disorders. Glaucomatous optic neuropathies, a leading cause of blindness, are characterized by the progressive loss of a selective population of retinal neurons, i.e., the retinal ganglion cells (RGCs). Here we review the current literature on the role of autophagy in the pathogenic process that leads to the degeneration of RGC in various experimental models of glaucoma exploring the modulation of the pathway as a potential therapeutic intervention.

Pattern of triptans use: a retrospective prescription study in Calabria, Italy.

Triptans are 5-hydroxytryptamine 1B/1D receptor agonists used in moderate to severe migraine attacks as first line when non-specific, symptomatic, nonsteroidal anti-inflammatory drugs are not effective. To gain insight in the treatment of migraine in the regional context, this retrospective (from January to August of the years 2017 and 2018) study aimed at monitoring the use of triptans approved by the regional health authority in Calabria. The data demonstrate that the overall treatment of migraine with triptans in the different provinces of Calabria falls in the average regional prescription/dispensation. Interestingly, Crotone showed a trend to an increased amount of defined daily dose/1000 inhabitants per day. The present analysis might stand for homogeneity of treatment of migraineurs in Calabria and highlights the need for better understanding the apparent differences in the local pattern of almotriptan use to improve the appropriateness.

Anxiolytic-Like Effects of Bergamot Essential Oil Are Insensitive to Flumazenil in Rats.

Anxiety disorders are one of the most common mental disorders, and benzodiazepines (BDZs), acting on gamma-aminobutyric acid type A (GABA-A) receptor complex, represent the most common antianxiety medications in the world. However, chronic BDZ use elicits several adverse reactions. Reportedly, aromatherapy is safer for the management of anxiety. Bergamot essential oil (BEO) extracted from Citrus bergamia Risso et Poiteau fruit, like other essential oils, is widely used in aromatherapy to relieve symptoms of stress-induced anxiety. Interestingly, preclinical data indicate that BEO induces anxiolytic-like/relaxant effects in animal behavioural tasks not superimposable to those of benzodiazepine diazepam. To better elucidate the involvement of GABAergic transmission, the present study examines the effects of pretreatment with flumazenil (FLZ), a benzodiazepine site antagonist, on BEO effects using open-field task (OFT) in rats. The data yielded show that FLZ does not significantly affect behavioural effects of the phytocomplex. These results demonstrate the lack of overlapping between BEO and BDZ behavioural effects, contributing to the characterization of the neurobiological profile of the essential oil for its rational use in aromatherapy.

Neuropharmacology of the Neuropsychiatric Symptoms of Dementia and Role of Pain: Essential Oil of Bergamot as a Novel Therapeutic Approach.

Aging of the population makes of dementia a challenge for health systems worldwide. The cognitive disturbance is a serious but not the only issue in dementia; behavioral and psychological syndromes known as neuropsychiatric symptoms of dementia remarkably reduce the quality of life. The cluster of symptoms includes anxiety, depression, wandering, delusions, hallucinations, misidentifications, agitation and aggression. The pathophysiology of these symptoms implicates all the neurotransmitter systems, with a pivotal role for the glutamatergic neurotransmission. Imbalanced glutamatergic and GABAergic neurotransmissions, over-activation of the extrasynaptic N-methyl-D-aspartate (NMDA) receptors and alterations of the latter have been linked to the development of neuropsychiatric symptoms experienced by almost the entire demented population. Drugs with efficacy and safety for prevention or long term treatment of these disorders are not available yet. Aromatherapy provides the best evidence for positive outcomes in the control of agitation, the most resistant symptom. Demented patients often cannot verbalize pain, resulting in unrelieved symptoms and contributing to agitation. Bergamot essential oil provides extensive preclinical evidence of analgesic properties. Incidentally, the essential oil of bergamot induces anxyolitic-like effects devoid of sedation, typical of benzodiazepines, with a noteworthy advantage for demented patients. These data, together with the reported safety profile, form the rational basis for bergamot as a neurotherapeutic to be trialed for the control of behavioral and psychological symptoms of dementia.

New Trends in Migraine Pharmacology: Targeting Calcitonin Gene-Related Peptide (CGRP) With Monoclonal Antibodies.

Migraine is a common neurologic disorder characterized by attacks consisting of unilateral, throbbing headache accompanied by photophobia, phonophobia, and nausea which remarkably reduces the patients' quality of life. Not migraine-specific non-steroidal anti-inflammatory drugs (NSAIDs) are effective in patients affected by mild episodic migraine whilst in moderate or severe episodic migraine and in chronic migraineurs triptans and preventative therapies are needed. Since these treatments are endowed with serious side effects and have limited effectiveness new pharmacological approaches have been investigated. The demonstrated pivotal role of calcitonin gene-related peptide (CGRP) has fostered the development of CGRP antagonists, unfortunately endowed with liver toxicity, and monoclonal antibodies (mAbs) toward circulating CGRP released during migraine attack or targeting its receptor. Currently, four mAbs, eptinezumab, fremanezumab, galcanezumab for CGRP and erenumab for CGRP canonical receptor, have been studied in clinical trials for episodic and chronic migraine. Apart from the proven effectiveness, these antibodies have resulted well tolerated and could improve the compliance of the patients due to their long half-lives allowing less frequent administrations. This study aims at investigating the still poorly clear pathogenesis of migraine and the potential role of anti-CGRP mAbs in the scenario of prophylaxis of migraine.

The tricyclic antidepressant clomipramine inhibits neuronal autophagic flux.

Antidepressants are commonly prescribed psychotropic substances for the symptomatic treatment of mood disorders. Their primary mechanism of action is the modulation of neurotransmission and the consequent accumulation of monoamines, such as serotonin and noradrenaline. However, antidepressants have additional molecular targets that, through multiple signaling cascades, may ultimately alter essential cellular processes. In this regard, it was previously demonstrated that clomipramine, a widely used FDA-approved tricyclic antidepressant, interferes with the autophagic flux and severely compromises the viability of tumorigenic cells upon cytotoxic stress. Consistent with this line of evidence, we report here that clomipramine undermines autophagosome formation and cargo degradation in primary dissociated neurons. A similar pattern was observed in the frontal cortex and liver of treated mice, as well as in the nematode Caenorhabditis elegans exposed to clomipramine. Together, our findings indicate that clomipramine may negatively regulate the autophagic flux in various tissues, with potential metabolic and functional implications for the homeostatic maintenance of differentiated cells.