Changes in Sleep Duration and Sleep Timing in the General Population from before to during the First COVID-19 Lockdown: A Systematic Review and Meta-Analysis.

BACKGROUND: The COVID-19 lockdown had a profound effect on everyday life, including sleep health. This systematic review and meta-analysis evaluated changes in quantitative sleep parameters during the first lockdown compared with pre-lockdown in the general population. METHODS: A search in scientific databases was performed to identify eligible observational studies from inception to 8 February 2023. We performed a random effects meta-analysis of those studies reporting (a) means of sleep duration, time in bed (TIB), and sleep timing (bedtime and wake-up time); (b) the percentages of atypical sleep duration before and during the lockdown; (c) the percentages of change in sleep duration and sleep timing. RESULTS: A total of 154 studies were included. A small increase in sleep duration (0.25 standardized mean difference, 95% CI 0.180-0.315) was found, with 55.0% of the individuals reporting changes, predominantly an increase (35.2%). The pooled relative risk for sleeping more than 8/9 h per night was 3.31 (95% IC 2.60-4.21). There was a moderately significant delay in sleep timing and a surge in napping. CONCLUSION: An increase in sleep duration and napping, and delayed sleep timing were observed. High-quality studies should evaluate whether these parameters have now become chronic or have returned to pre-lockdown values.

Polypharmacy, drug-drug interactions, anticholinergic burden and cognitive outcomes: a snapshot from a community-dwelling sample of older men and women in northern Italy.

Polypharmacy (PP) use is very common in older people and may lead to drug-drug interactions (DDIs) and anticholinergic burden (ACB) that may affect cognitive function. We aimed to determine the occurrence of PP, potential DDIs and ACB and their role in cognitive outcomes in an older population. Cross-sectional data from 636 community-dwelling adults (73.2 ± 6.0 SD, 58.6% women) participating in the NutBrain study (2019-2023) were analyzed. Participants were asked about their medication use, and data on potential DDIs and ACB were extracted. The associations of PP (≥ 5 drugs/day), potential DDIs, and ACB with mild cognitive impairment (MCI) and specific cognitive domains were assessed using logistic regression adjusted for confounders. Sex-stratified analysis was performed. Overall, 27.2% of the participants were exposed to PP, 42.3% to potential DDIs and 19% to cumulative ACB. Women were less exposed to PP and more exposed to ACB than men. In multivariate analysis, the odds of having MCI (24%) were three times higher in those with severe ACB (≥ 3) (OR 3.34, 95%CI 1.35-8.25). ACB was positively associated with poor executive function (OR 4.45, 95%CI 1.72-11.49) and specifically with the Frontal Assessment Battery and neuropsychological tests of phonological and semantic fluency. In sex-stratified analysis, ACB was statistically significantly associated with MCI and executive function in women and with memory in men. PP, potential DDIs and anticholinergics use are very common in community-dwelling older people. ACB exposure is associated with MCI, particularly with poor executive function. Clinicians are encouraged to be vigilant when prescribing anticholinergics.Trial registration: Trial registration number NCT04461951, date of registration July 7, 2020 (retrospectively registered, ClinicalTrials.gov).

Adherence to Mediterranean diet is inversely associated with depressive symptoms in older women: findings from the NutBrain Study.

Data on the association of the Mediterranean diet (MD) with depressive symptoms in older people at high risk of depression are scarce. This study aimed to investigate the cross-sectional association of the adherence to the MD and its components with depressive symptoms in an Italian cohort of older men and women. A total of 325 men and 473 women aged 65­97 years (2019­2023) answered a 102-item semi-quantitative FFQ, which was used to calculate the Mediterranean diet score (MDS). Depressive symptoms were assessed using the Centre for Epidemiological Studies Depression Scale; subjects with a score of 16 or more were considered to have depression. Multivariable logistic regression was used for statistical analysis. The occurrence of depressive symptoms was 19·8 % (8·0 % men, 27·9 % women). High adherence to MDS (highest tertile) significantly reduced the odds of having depressive symptoms by 54·6 % (OR 0·454, 95 % CI 0·266, 0·776). In sex-stratified analysis, the reduction was evident in women (OR 0·385, 95 % CI 0·206, 0·719) but not in men (OR 0·828, 95 % CI 0·254, 2·705). Looking at the association of MDS components with depressive symptoms, we found an inverse significant association with fish consumption and the MUFA:SFA ratio above the median only in women (OR 0·444, 95 % CI 0·283, 0·697 and OR 0·579, 95 % CI 0·345, 0·971, respectively). High adherence to the MDS, and a high fish intake and MUFA:SFA ratio were associated with lower depressive symptoms in women only. Future longitudinal studies are needed to confirm these findings and to explore the underlying biological mechanisms.

Investigating the individual and joint effects of socioeconomic status and lifestyle factors on mild cognitive impairment in older Italians living independently in the community: results from the NutBrain study.

OBJECTIVES: Despite extensive research, a clear understanding of the role of the interaction between lifestyle and socioeconomic status (SES) on cognitive health is still lacking. We investigated the joint association of socioeconomic factors in early to midlife and lifestyle in later life and Mild Cognitive Impairment (MCI). DESIGN: Observational cross-sectional study. SETTING: NutBrain study in northern Italy. PARTICIPANTS: 773 community-dwelling adults aged 65 years and older (73.2 ± 6.0 SD, 58.6% females) participating in the NutBrain study (2019-2023). MEASUREMENTS: Three SES indicators (home ownership, educational level, occupation) and five lifestyle factors (adherence to Mediterranean diet, physical activity, smoking habits, social network, leisure activities) were selected. Each factor was scored and summed to calculate SES and healthy lifestyle scores; their joint effect was also examined. The association with MCI was assessed by logistic regression controlling for potential confounders. Sex-stratified analysis was performed. RESULTS: In total, 24% of the subjects had MCI. The multivariable logistic model showed that a high SES and a high lifestyle score were associated with 81.8% (OR0.182; 95%CI 0.095-0.351), and 44.1% (OR0.559; 95%CI 0.323-0.968) lower odds of having MCI, respectively. When examining the joint effect of SES and lifestyle factors, the cognitive benefits of a healthy lifestyle were most pronounced in participants with low SES. A healthier lifestyle score was found to be significantly associated with lower odds of MCI, only in females. CONCLUSIONS: According to our findings, SES was positively associated with preserved cognitive function, highlighting the importance of active lifestyles in reducing socioeconomic health inequalities, particularly among those with a relatively low SES. TRIAL REGISTRATION: Trial registration number NCT04461951, date of registration July 7, 2020 (retrospectively registered, ClinicalTrials.gov).

Changes in sleep quality and sleep disturbances in the general population from before to during the COVID-19 lockdown: A systematic review and meta-analysis.

Introduction: This systematic review and meta-analysis aims to explore changes in sleep quality and sleep disturbances in the general population from before to during the COVID-19 lockdown. Methods: The protocol was registered in PROSPERO (CRD42021256378) and the PRISMA guidelines were followed. The major databases and gray literature were systematically searched from inception to 28/05/2021 to identify observational studies evaluating sleep changes in the general population during the lockdown with respect to the pre-lockdown period. A random effects meta-analysis was undertaken for studies reporting (a) the means of the Pittsburgh Sleep Quality Index (PSQI) global scores or the means of the sleep onset latency (SOL) times (minutes - min) before and during the lockdown, (b) the percentages of poor sleep quality before and during the lockdown, or (c) the percentages of changes in sleep quality. Subgroup analysis by risk of bias and measurement tool utilized was carried out. A narrative synthesis on sleep efficiency, sleep disturbances, insomnia and sleep medication consumption was also performed. Results: Sixty-three studies were included. A decline in sleep quality, reflected in a pooled increase in the PSQI global scores (standardized mean difference (SMD) = 0.26; 95% CI 0.17-0.34) and in SOL (SMD = 0.38 min; 95% CI 0.30-0.45) were found. The percentage of individuals with poor sleep quality increased during the lockdown (pooled relative risk 1.4; 95% CI 1.24-1.61). Moreover, 57.3% (95% CI 50.01-61.55) of the individuals reported a change in sleep quality; in 37.3% (95% CI 34.27-40.39) of these, it was a worsening. The studies included in the systematic review reported a decrease in sleep efficiency and an increase in sleep disturbances, insomnia, and in sleep medication consumption. Discussion: Timely interventions are warranted in view of the decline in sleep quality and the increase in sleep disturbances uncovered and their potentially negative impact on health. Further research and in particular longitudinal studies using validated instruments examining the long-term impact of the lockdown on sleep variables is needed. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021256378, identifier CRD42021256378.

Pre-existing mental health disorders and fear of COVID-19 pandemic: Data from a phone survey in community-dwelling older adults recruited in the NutBrain study.

Background: COVID-19 has caused a parallel epidemic of fear, anxiety, depression, stress, and frustration, particularly among the most fragile and vulnerable individuals, such as older people and those with previous mental health disorders. The present study aims to investigate the association between pre-existing mental health disorders, particularly depressive symptoms and Mild Cognitive Impairment (MCI), and the fear of COVID-19 and to explore which cognitive domains were involved in coping with fear in older people. Materials and methods: In April 2020, we conducted a phone-interview questionnaire on community-dwelling older adults living in Lombardy Region (Italy) who participated in the NutBrain study. At baseline, socio-demographic characteristics along with lifestyles, and medical history were recorded. Participants underwent a neuropsychological battery exploring the global cognitive function and specific cognitive domains, to detect cases of MCI. The Center for Epidemiologic Studies Depression scale (CES-D) was used for screening depressive symptoms. During the phone survey, respondents were assessed using a structured questionnaire querying about fear of the COVID-19 pandemic. We performed multivariate logistic regression models to study the association between MCI and depressive symptomatology and fear. We also explored which cognitive domains were associated with fear. Odds Ratios (OR) with Confidence Intervals (95%CI) were estimated adjusting for potential confounders. Results: Out of the 351 respondents (mean age 73.5 ± 6.1 years, 59.8% women, 49.1% high education), at baseline, 22.9% had MCI and 18.8% had depressive symptoms. In the multivariate analyses gender, age, and body mass index were significantly associated with the fear score. Considering different domains of fear, MCI was associated with fear of being infected themselves (OR 2.55, 95%CI 1.39-4.70) while depressive symptoms were associated with fear of contagion for family members (OR 2.38, 95%CI 1.25-4.52). Impaired executive cognitive function was positively associated with the highest tertile of the fear score (OR 3.28, 95%CI 1.37-7.74) and with fear of contagion for themselves (OR 3.39, 95%CI 1.61-7.17). Conclusion: Older adults experienced different fear reactions, particularly when suffering from neurocognitive disorders and depressive symptoms; executive dysfunction was associated with increased fear. These results highlighted the need to pay attention to the psychological effects of the outbreak of COVID-19 to target intervention, especially among vulnerable subgroups of individuals. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT04461951].

PROtein enriched MEDiterranean diet to combat undernutrition and promote healthy neuroCOGnitive ageing in older adults: The PROMED-COG consortium project.

Dementia is a major public health challenge owing to its increasing prevalence and recognised impact on disability among older adults. Observational data indicate that weight loss is associated with increased dementia risk of 30%-40% and precedes a diagnosis of cognitive impairment or dementia by at least one decade. Although relatively little is known about the mechanisms of unintentional weight loss in dementia, this provides a window of opportunity to intervene with strategies to counteract undernutrition and delay, or prevent, the onset of dementia. This article provides an overview of the PROMED-COG project and associated work packages. The project aimes to (1) strengthen the epidemiologic evidence to better understand the potential benefits of combating undernutrition for healthy neurocognitive ageing; (2) increase scientific knowledge on the balance between a protein enriched Mediterranean diet (PROMED) and physical exercise to prevent undernutrition and promote healthy neurocognitive ageing, and generate data on mechanistic pathways; (3) stimulate collaboration and capacity building for nutrition and neurocognitive ageing research in Europe; and (4) develop public and practice recommendations to combat undernutrition and promote healthy neurocognitive ageing in older adults. Findings will provide new and critical insights into the role of undernutrition in neurocognitive ageing, how this role can differ by sex, genetic risk and timing of undernutrition exposure, and how modifications of dietary and physical activity behaviour can reduce the burden of undernutrition and neurodegeneration. The research outcomes will be useful to inform policy and practice about the dietary guidelines of older people and provide insight to industry for the development of food-based solutions to prevent undernutrition.

Naturally Degradable Photonic Devices with Transient Function by Heterostructured Waxy-Sublimating and Water-Soluble Materials.

Combined dry-wet transient materials and devices are introduced, which are based on water-dissolvable dye-doped polymers layered onto nonpolar cyclic hydrocarbon sublimating substrates. Light-emitting heterostructures showing amplified spontaneous emission are obtained on transient elements and used as illumination sources for speckle-free, full-field imaging, and transient optical labels are realized that incorporate QR-codes with stably encoded information. The transient behavior is also studied at the microscopic scale, highlighting the real-time evolution of material domains in the sublimating compound. Finally, the exhausted components are fully soluble in water thus being naturally degradable. This technology opens new and versatile routes for environmental sensing, storage conditions monitoring, and organic photonics.

Low-voltage 2D materials-based printed field-effect transistors for integrated digital and analog electronics on paper.

Paper is the ideal substrate for the development of flexible and environmentally sustainable ubiquitous electronic systems, which, combined with two-dimensional materials, could be exploited in many Internet-of-Things applications, ranging from wearable electronics to smart packaging. Here we report high-performance MoS2 field-effect transistors on paper fabricated with a "channel array" approach, combining the advantages of two large-area techniques: chemical vapor deposition and inkjet-printing. The first allows the pre-deposition of a pattern of MoS2; the second, the printing of dielectric layers, contacts, and connections to complete transistors and circuits fabrication. Average ION/IOFF of 8 × 103 (up to 5 × 104) and mobility of 5.5 cm2 V-1 s-1 (up to 26 cm2 V-1 s-1) are obtained. Fully functional integrated circuits of digital and analog building blocks, such as logic gates and current mirrors, are demonstrated, highlighting the potential of this approach for ubiquitous electronics on paper.

Inkjet-printed graphene Hall mobility measurements and low-frequency noise characterization.

We report room temperature Hall mobility measurements, low temperature magnetoresistance analysis and low-frequency noise characterization of inkjet-printed graphene films on fused quartz and SiO2/Si substrates. We found that thermal annealing in vacuum at 450 °C is a necessary step in order to stabilize the Hall voltage across the devices, allowing their electrical characterization. The printed films present a minimum sheet resistance of 23.3 Ω sq-1 after annealing, and are n-type doped, with carrier concentrations in the low 1020 cm-3 range. The charge carrier mobility is found to increase with increasing film thickness, reaching a maximum value of 33 cm2 V-1 s-1 for a 480 nm-thick film printed on SiO2/Si. Low-frequency noise characterization shows a 1/f noise behavior and a Hooge parameter in the range of 0.1-1. These results represent the first in-depth electrical and noise characterization of transport in inkjet-printed graphene films, able to provide physical insights on the mechanisms at play.

Use of enteroscope without the overtube in incomplete colonoscopies.

Objectives: Colonoscopy is the gold standard diagnostic method for colorectal cancer (CRC) screening. Despite the progress in the endoscopy technology field, a small percentage of colonoscopies is still incomplete. The reasons for that are mostly associated with anatomic features, such as fixed, angulated, long and loopy colon, intra-abdominal adherences and female gender. To overcome such difficulties, the usefulness of scopes different from conventional adult colonoscope (CF), such as paediatric colonoscope (PCF), gastroscope (GIF), single and double balloon enteroscope (SBE and DBE, respectively), has been shown in literature. Our retrospective study aims to evaluate the caecal intubation rate using a SBE without the overtube in patients who previously underwent an incomplete procedure with a different scope.Methods: Patients with a previous incomplete colonoscopy with CF, PCF or GIF were retrospectively enrolled through the analysis of a dedicated database. The enteroscope used was the Olympus Enteropro Single Balloon SiF-Q180 with no overtube. Complete colonoscopy was defined as successful caecal intubation.Results: SBE was used to scope 47 adult patients, mostly female, and it led to a complete procedure in 91% of them. The most frequent reason for an incomplete procedure even with the use of SBE was a fixed and angulated colon.Conclusions: Colonoscopy performed with SBE was safe and no adverse events during and/or after the procedure occurred. Our results suggest that SBE with no overtube is a useful and valid alternative to other type of scopes in difficult cases, especially those related to fixed/angulated colon and in female gender.

The use of single balloon enteroscopy in Crohn's disease and its impact on clinical outcome.

OBJECTIVES: Single balloon enteroscopy (SBE) is an effective and safe modality for the diagnosis and therapeutic intervention of small bowel disorders. Its use in patients with Crohn's disease (CD) and particularly its effect on management changes in CD have not yet been determined. MATERIALS AND METHODS: We performed a retrospective review of the endoscopic and clinical data available on a cohort of patients with small bowel CD who had undergone SBE to determine the diagnostic and therapeutic yield of the procedure and the initial and longer-term impact it had on clinical management. RESULTS: About 52 patients have undergone SBE in our unit for the investigation of known (n = 39) or suspected (n = 13) small bowel CD with a diagnostic yield of 77% and 39%, respectively. SBE had an immediate clinical impact in 69% (n = 33) of patients, including dilatation of a stricture in 27% (n = 13), initiation or adjustment of dose of medications in 48% (n = 23), referral for surgical resection in 6% (n = 3). Moreover, the procedure permitted determining a new diagnosis of CD in 8% of the patients (n = 4), and excluding it in 8% (n = 4). Longer term follow-up was available in 34 patients (65%) which showed a significant difference in mean HBI score from 6.6 before the procedure to 4.2 after it (p < .0001). CONCLUSIONS: SBE has a high diagnostic and therapeutic yield in CD and significantly impacts disease management. Careful patient selection is a key factor in optimizing its use in CD.

Amyloid-ß Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory.

High levels of amyloid-ß peptide (Aß) have been related to Alzheimer's disease pathogenesis. However, in the healthy brain, low physiologically relevant concentrations of Aß are necessary for long-term potentiation (LTP) and memory. Because cGMP plays a key role in these processes, here we investigated whether the cyclic nucleotide cGMP influences Aß levels and function during LTP and memory. We demonstrate that the increase of cGMP levels by the phosphodiesterase-5 inhibitors sildenafil and vardenafil induces a parallel release of Aß due to a change in the approximation of amyloid precursor protein (APP) and the ß-site APP cleaving enzyme 1. Moreover, electrophysiological and behavioral studies performed on animals of both sexes showed that blocking Aß function, by using anti-murine Aß antibodies or APP knock-out mice, prevents the cGMP-dependent enhancement of LTP and memory. Our data suggest that cGMP positively regulates Aß levels in the healthy brain which, in turn, boosts synaptic plasticity and memory.SIGNIFICANCE STATEMENT Amyloid-ß (Aß) is a key pathogenetic factor in Alzheimer's disease. However, low concentrations of endogenous Aß, mimicking levels of the peptide in the healthy brain, enhance hippocampal long-term potentiation (LTP) and memory. Because the second messenger cGMP exerts a central role in LTP mechanisms, here we studied whether cGMP affects Aß levels and function during LTP. We show that cGMP enhances Aß production by increasing the APP/BACE-1 convergence in endolysosomal compartments. Moreover, the cGMP-induced enhancement of LTP and memory was disrupted by blockade of Aß, suggesting that the physiological effect of the cyclic nucleotide on LTP and memory is dependent upon Aß.

A novel role of c-FLIP protein in regulation of ER stress response.

Cellular-Flice-like inhibitory protein (c-FLIP) is an apoptosis modulator known to inhibit the extrinsic apoptotic pathway thus blocking Caspase-8 processing in the Death Inducing Signalling Complex (DISC). We previously demonstrated that c-FLIP localizes at the endoplasmic reticulum (ER) and that c-FLIP-deficient mouse embryonic fibroblasts (MEFs) display an enlarged ER morphology. In the present study, we have addressed the consequences of c-FLIP ablation in the ER stress response by investigating the effects of pharmacologically-induced ER stress in Wild Type (WT) and c-FLIP-/- MEFs. Surprisingly, c-FLIP-/- MEFs were found to be strikingly more resistant than WT MEFs to ER stress-mediated apoptosis. Analysis of Unfolded Protein Response (UPR) pathways revealed that Pancreatic ER Kinase (PERK) and Inositol-Requiring Enzyme 1 (IRE1) branch signalling is compromised in c-FLIP-/- cells when compared with WT cells. We found that c-FLIP modulates the PERK pathway by interfering with the activity of the serine threonine kinase AKT. Indeed, c-FLIP-/- MEFs display higher levels of active AKT than WT MEFs upon ER stress, while treatment with a specific AKT inhibitor of c-FLIP-/- MEFs subjected to ER stress restores the PERK but not the IRE1 pathway. Importantly, the AKT inhibitor or dominant negative AKT transfection sensitizes c-FLIP-/- cells to ER stress-induced cell death while the expression of a constitutively active AKT reduces WT cells sensitivity to ER stress-induced death. Thus, our results demonstrate that c-FLIP modulation of AKT activity is crucial in controlling PERK signalling and sensitivity to ER stress, and highlight c-FLIP as a novel molecular player in PERK and IRE1-mediated ER stress response.

Cancer Microenvironment and Endoplasmic Reticulum Stress Response.

Different stressful conditions such as hypoxia, nutrient deprivation, pH changes, or reduced vascularization, potentially able to act as growth-limiting factors for tumor cells, activate the unfolded protein response (UPR). UPR is therefore involved in tumor growth and adaptation to severe environments and is generally cytoprotective in cancer. The present review describes the molecular mechanisms underlying UPR and able to promote survival and proliferation in cancer. The critical role of UPR activation in tumor growth promotion is discussed in detail for a few paradigmatic tumors such as prostate cancer and melanoma.

c-Flip KO fibroblasts display lipid accumulation associated with endoplasmic reticulum stress.

c-Flip proteins are well-known apoptosis modulators. They generally contribute to tissue homeostasis maintenance by inhibiting death-receptor-mediated cell death. In the present manuscript, we show that c-Flip knock-out (KO) mouse embryonic fibroblasts (MEFs) kept in culture under starvation conditions gradually modify their phenotype and accumulate vacuoles, becoming progressively larger according to the duration of starvation. Large vacuoles are present in KO MEFs though not in WT MEFs, and are Oil Red-O positive, which indicates that they represent lipid droplets. Western blot experiments reveal that, unlike WT MEFs, KO MEFs express high levels of the lipogenic transcription factor PPAR-γ. Lipid droplet accumulation was found to be associated with endoplasmic reticulum (ER) stress activation and autophagic modulation valuated by means of BIP increase, LC3 lipidation and AMP-activated protein kinase (AMPK) phosphorylation, and p62 accumulation. Interestingly, XBP-1, an ER stress-induced lipogenic transcription factor, was found to preferentially localize in the nucleus rather than in the cytoplasm of KO MEFs. These data demonstrate that, upon starvation, c-Flip affects lipid accumulation, ER stress and autophagy, thereby pointing to an important role of c-Flip in the adaptive response and ER stress response programs under both normal and pathological conditions.

Montreal Cognitive Assessment (MoCA)-Italian version: regression based norms and equivalent scores.

The Montreal Cognitive Assessment (MoCA) is a brief cognitive screening instrument developed by Nasreddine et al. to detect mild cognitive impairment, a high-risk condition for Alzheimer's disease and other forms of dementia. In this study we report normative data on the MoCA-Italian version, collected on a sample of 225 Italian healthy subjects ranged in age between 60 and 80 years, and in formal education from 5 to 23 years. The global normal cognition was established in accordance with the Mini-Mental State Examination score and with the Prose Memory Test score (Spinnler and Tognoni, Ital J Neurol Sci 6:25-27, 1987). None of the participants had a history of psychiatric, neurological, cerebrovascular disorders or brain injury or took drugs affecting cognition. Linear regression analysis was performed to evaluate the potential effect of age, education and sex on the MoCA total performance score. We provide correction grids to adjust raw scores and equivalent scores with cut-off value to allow comparison between MoCA performance and others neuropsychological test scores that can be administered on the same subject.

Autophagy in prostate cancer and androgen suppression therapy.

The role of autophagy is known to be highly complex and context-dependent, leading to both cancer suppression and progression in several tumors including melanoma, breast and prostate cancer. In the present review, recent advances in an understanding of the involvement of autophagy in prostate cancer treatment are described. The regulatory effects of androgens on prostate cancer cell autophagy are particularly discussed in order to highlight the effects of autophagy modulation during androgen deprivation. A critical evaluation of the studies examined in the present review suggests the attractive possibility of autophagy inhibition combined with hormonal therapy as a promising approach for prostate cancer treatment.

Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw.

Cannabidiol, the major non-psychoactive component of marijuana, has various pharmacological actions of clinical interest. It is reportedly effective as an anti-inflammatory and anti-arthritic in murine collagen-induced arthritis. The present study examined the anti-inflammatory and anti-hyperalgesic effects of cannabidiol, administered orally (5-40 mg/kg) once a day for 3 days after the onset of acute inflammation induced by intraplantar injection of 0.1 ml carrageenan (1% w/v in saline) in the rat. At the end of the treatment prostaglandin E2 (PGE2) was assayed in the plasma, and cyclooxygenase (COX) activity, production of nitric oxide (NO; nitrite/nitrate content), and of other oxygen-derived free radicals (malondialdehyde) in inflamed paw tissues. All these markers were significantly increased following carrageenan. Thermal hyperalgesia, induced by carrageenan and assessed by the plantar test, lasted 7 h. Cannabidiol had a time- and dose-dependent anti-hyperalgesic effect after a single injection. Edema following carrageenan peaked at 3 h and lasted 72 h; a single dose of cannabidiol reduced edema in a dose-dependent fashion and subsequent daily doses caused further time- and dose-related reductions. There were decreases in PGE2 plasma levels, tissue COX activity, production of oxygen-derived free radicals, and NO after three doses of cannabidiol. The effect on NO seemed to depend on a lower expression of the endothelial isoform of NO synthase. In conclusion, oral cannabidiol has a beneficial action on two symptoms of established inflammation: edema and hyperalgesia.

Therapeutic effect of the endogenous fatty acid amide, palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems.

1. The anti-inflammatory activity of the endogenous fatty acid amide palmitoylethanolamide and its relationship to cyclo-oxygenase (COX) activity, nitric oxide (NO) and oxygen free radical production were investigated in the rat model of carrageenan-induced acute paw inflammation and compared with the nonsteroidal anti-inflammatory drug (NSAID) indomethacin. 2. Palmitoylethanolamide (1, 3, 5, 10 mg kg(-1); p.o.) and indomethacin (5 mg kg(-1); p.o.) were administered daily after the onset of inflammation for three days and the paw oedema was measured daily; 24 h after the last dose (fourth day) the rats were killed and the COX activity and the content of nitrite/nitrate (NO(2)(-)/NO(3)(-)), malondialdehyde (MDA), endothelial and inducible nitric oxide synthase (eNOS and iNOS) were evaluated in the paw tissues. 3. Palmitoylethanolamide had a curative effect on inflammation, inhibiting the carrageenan-induced oedema in a dose- and time-dependent manner. This effect was not reversed by the selective CB(2) receptor antagonist (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide) (SR144528), 3 mg kg(-1) p.o. On the fourth day after carrageenan injection, COX activity and the level of NO(2)(-)/NO(3)(-), eNOS and MDA were increased in the inflamed paw, but iNOS was not present. Palmitoylethanolamide (10 mg kg(-1)) and indomethacin markedly reduced these increases. 4. Our findings show, for the first time, that palmitoylethanolamide has a curative effect in a model of acute inflammation. The inhibition of COX activity and of NO and free radical production at the site of inflammation might account for this activity.