2-pentadecyl-2-oxazoline prevents cognitive and social behaviour impairments in the Amyloid ß-induced Alzheimer-like mice model: Bring the α2 adrenergic receptor back into play.

The 2-pentadecyl-2-oxazoline (PEA-OXA) is a natural compound with protective action in neuro-inflammation. We have previously shown that PEA-OXA behaves as an α2 adrenergic receptor (α2AR) antagonist and a putative protean agonist on histamine H3 receptors. Recently, neuroinflammation and monoaminergic neurotransmission dysfunction has drawn particular attention in Alzheimer Disease (AD) pathophysiology. In this context, the objective of this study was to investigate the effects of the dual-acting PEA-OXA in an AD-like model in mice. A combined computational and experimental approach was used to evaluate the ability of PEA-OXA to bind α2A-AR subtype, and to investigate the effects of PEA-OXA treatment on neuropathological (behavioural and functional) effects induced by soluble Amyloid ß 1-42 (sAß1-42) intracerebroventricular injection. Computational analysis revealed the PEA-OXA ability to bind the α2A-AR, a pharmacological target for AD, in two alternative poses, one overlapping the Na+ binding site. In vivo studies indicated that chronic treatment with PEA-OXA (10 mg/kg, os) restored the cognitive (discriminative and spatial memory) deficits and social impairments induced by sAß injection. Consistently, electrophysiological analysis showed a recovery of the long-term potentiation in the hippocampus (Lateral Entorhinal Cortex-Dentate Gyrus pathway), while neuroinflammation, i.e., increased pro-inflammatory cytokines levels and microglia cells density were reduced. These data provide the basis for further investigation of the pro-cognitive aptitude of PEA-OXA by proposing it as an adjuvant in the treatment in AD, for which the available pharmacological approaches remain unsatisfactory. Moreover, this study offers new future direction in research investigating the role of α2AR in neuropsychiatric illness and therapies.

NAbiximols Clinical Translation To the treatment of Pain and Agitation In Severe Dementia (NACTOPAISD): Clinical trial protocol.

Up to 80 % nursing home residents with dementia experiences chronic pain. Contextually, 97 % presents fluctuant neuropsychiatric symptoms (NPS). Among the most challenging is agitation, connected with undertreated pain and managed through neuroleptics doubling death risk. Evidence is accumulating in favor of the involvement of the endocannabinoid system in nociception and NPS. This double-blind, placebo-controlled, randomized trial (NAbiximols Clinical Translation To the treatment of Pain and Agitation In Severe Dementia [NACTOPAISD]) aims at investigating efficacy and safety of oral spray nabiximols, containing Δ9-tetrahydrocannabinol and cannabidiol (Sativex®), for pain and agitation treatment in severe dementia patients (Mini-Mental State Examination ≤ 12) over 65. The coprimary endpoints are efficacy on pain and agitation, assessed through the recently validated Italian Mobilization-Observation-Behavior-Intensity-Dementia and the Cohen-Mansfield Agitation Inventory. The secondary endpoint is the evaluation of efficacy duration after wash-out and the assessment of quality of life through the DEMQOL. Any adverse events will be reported. The results undergo statistical analysis plan. NACTOPAISD might provide rationale for a translational safer pain and agitation treatment in severe dementia. It is approved by Calabria Region Ethics Committee and follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) and the Consolidated Standards of Reporting Trials (CONSORT) statements.

Fetal dose estimation for Virtual Tangential-fields Arc Therapy whole breast irradiation by optically stimulated luminescence dosimeters.

Breast cancer is the most frequently diagnosed tumor in pregnant women and radiation therapy should carefully be weighted up because of the dose to the fetus. The aim of this study was to investigate fetal dose in a patient treated with Virtual Tangential-fields Arc Therapy (ViTAT), an innovative technique for whole breast irradiation. Optically stimulated luminescence detectors (OSLDs) were calibrated on a Varian TrueBeam linac, with both a 6X and 6XFFF beam quality, and used for out-of-field measurements. Fetal dose related with ViTAT technique was compared to the standard 3D conformal radiation therapy technique (3DCRT). The fetal dose delivered with a ViTAT technique planned with 6XFFF beam was also investigated. Measurements were taken on a phantom composed of Rando Alderson Phantom slices and solid water slabs. OSLDs were placed in a region identified by the height of the fundus from conception to the twentieth week using a custom made PMMA grid. Due to the higher number of monitor units, the peripheral dose of ViTAT delivered with 6X beams is higher than that of 3DCRT. However, nanoDots measurements prove that ViTAT can be used in place of 3DCRT while maintaining similar fetal dose levels if 6XFFF beams are used.

Is there a rational basis for cannabinoids research and development in ocular pain therapy? A systematic review of preclinical evidence.

BACKGROUND: Purpose of the present systematic review is to investigate preclinical evidence in favor of the working hypothesis of efficacy of cannabinoids in ocular pain treatment. METHODS: Literature search includes the most relevant repositories for medical scientific literature from inception until November, 24 2021. Data collection and selection of retrieved records adhere to PRISMA criteria. RESULTS: In agreement with a priori established protocol the search retrieved 2471 records leaving 479 results after duplicates removal. Eleven records result from title and abstract screening to meet the inclusion criteria; only 4 results are eligible for inclusion in the qualitative synthesis impeding meta-analysis. The qualitative analysis highlights the antinociceptive and anti-inflammatory efficacy of Δ8-tetrahydrocannabinol, cannabidiol and its derivative HU-308 and of new racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229. Moreover, CB2R agonists RO6871304 and RO6871085 and CB2R ligand HU910 provide evidence of anti-inflammatory efficacy. CB2 agonist HU308 reduces of 241% uveitis-induced leukocyte adhesion and changes lipidome profile. Methodological and design issues raise concern of risk of bias and the amount of studies is too small for generalization. Furthermore, the ocular pain model used can resemble only inflammatory but not neuropathic pain. CONCLUSIONS: The role of the endocannabinoid system in ocular pain is underinvestigated, since only two studies assessing the effects of cannabinoid receptors modulators on pain behavior and other two on pain-related inflammatory processes are found. Preclinical studies investigating the efficacy of cannabinoids in ocular inflammatory and neuropathic pain models are needed to pave the way for clinical translation.

Post-operative outcomes of different surgical approaches to oropharyngeal squamous cell cancer: a case-matched study.

OBJECTIVE: To compare the post-operative outcomes of transoral laser microsurgery, lateral pharyngotomy and transmandibular surgery in oropharyngeal cancer management. METHODS: Records of 162 patients treated with transmandibular surgery, transoral laser microsurgery or lateral pharyngotomy were reviewed. The transoral laser microsurgery cohort was matched with the lateral pharyngotomy and transmandibular surgery cohorts for tumour stage, tumour subsite and human papilloma virus status, and the intra- and post-operative outcomes were compared. RESULTS: Duration of surgery and hospital stay were significantly longer for transmandibular surgery. Tracheostomy and nasogastric feeding tube rates were similar, but time to decannulation and to oral feeding were longer in the transmandibular surgery group. Transmandibular surgery more frequently required flap reconstruction and had a greater complication rate. Negative margins were fewer in the lateral pharyngotomy group than in the transoral laser microsurgery and transmandibular surgery groups. CONCLUSION: In comparison with transmandibular surgery, transoral laser microsurgery and lateral pharyngotomy were associated with fewer complications and faster functional recovery. Lateral pharyngotomy had a higher rate of positive margins than transoral laser microsurgery, with a consequently greater need for adjuvant therapy. Many patients are nonetheless unsuitable for transoral surgery. All these factors should be considered when deciding on oropharyngeal cancer surgical treatment.

The Cold Case of Metabotropic Glutamate Receptor 6: Unjust Detention in the Retina?

It is a common opinion that metabotropic glutamate receptor subtype 6 (mGluR6) is expressed exclusively in the retina, and in particular in the dendrites of ON-bipolar cells. Glutamate released in darkness from photoreceptors activates mGluR6, which is negatively associated with a membrane non-selective cation channel, the transient receptor potential melanoma-related 1, TRPM1, resulting in cell hyperpolarization. The evidence that mGluR6 is expressed not only in the retina but also in other tissues and cell populations has accumulated over time. The expression of mGluR6 has been identified in microglia, bone marrow stromal and prostate cancer cells, B lymphocytes, melanocytes and keratinocytes and non-neural tissues such as testis, kidney, cornea, conjunctiva, and eyelid. The receptor also appears to be expressed in brain areas, such as the hypothalamus, cortex, hippocampus, nucleus of tractus solitarius, superior colliculus, axons of the corpus callosum and accessory olfactory bulb. The pharmacological activation of mGluR6 in the hippocampus produced an anxiolytic-like effect and in the periaqueductal gray analgesic potential. This review aims to collect all the evidence on the expression and functioning of mGluR6 outside the retina that has been accumulated over the years for a broader view of the potential of the receptor whose retinal confinement appears understimated.

Dose intercomparison at Italian hadrontherapy centers.

PURPOSE: To perform the first dosimetric intercomparison for proton beams in Italy using ionization chambers, according to the IAEA TRS-398 code of practice. METHODS: Measurement sites included: National Center for Oncological Hadron Therapy (CNAO, Pavia), Center for Proton Therapy (CTP, Trento) and Center for Hadron Therapy and for advanced Nuclear Applications (CATANA, Catania). For comparison we also included a 6 MV photon beam produced at Istituti Clinici Scientifici Maugeri (ICSM, Pavia). For proton beams, both single pseudo-monoenergetic layers (in order to obtain a planned dose of 2 Gy at the reference depth of 2 cm in a water phantom) and Spread-out Bragg peaks (SOBP) have been delivered. Measurements were performed with a PTW Farmer 30010-1 and a PTW Advanced Markus type 34,045 ionization chamber. RESULTS: Data obtained at CATANA, CNAO and CPT in terms of absorbed dose to water depth show good consistency within the experimental uncertainties, with a weighted mean of 1.99 ± 0.01 Gy and a standard error of 0.003 Gy, with reference to a nominal dose of 2 Gy as designed by the treatment planning system. CONCLUSIONS: The results showed a standard deviation of less than 1% for single layer and SOBP beams, for all chambers and a percent deviation less than 1.5% for single layer measurements. The weighted means of the absorbed doses for clinical proton beams (118.19 MeV and 173.61 MeV) are consistent within less than 1%. These results agree within the 1.5% difference considered acceptable for national dose intercomparison.

Mesenteric cyst and recurrent abdominal pain in a patient with Gorlin-Goltz syndrome: a case report.

Gorlin-Goltz syndrome (GGS) is an infrequent autosomal do-minant multisystemic disease with complete penetrance and variable expressivity. It is estimated to have an incidence of 1:50,000 - 1:150,000 cases with a M/F = 1:1. This report describes a case of recurrent abdominal pain due to a large mesenteric cyst in a 38-year-old female patient affected by a rare disease: Gorlin-Goltz syndrome.

Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice.

The microbiota-gut-brain axis (MGBA) regulates the reciprocal interaction between chronic inflammatory bowel and psychiatric disorders. This interaction involves multiple pathways that are highly debated. We examined the behavioural, biochemical and electrophysiological alterations, as well as gut microbiota composition in a model of antibiotic-induced experimental dysbiosis. Inflammation of the small intestine was also assessed. Mice were exposed to a mixture of antimicrobials for 2weeks. Afterwards, they received Lactobacillus casei DG (LCDG) or a vehicle for up to 7days via oral gavage. Perturbation of microbiota was accompanied by a general inflammatory state and alteration of some endocannabinoidome members in the gut. Behavioural changes, including increased immobility in the tail suspension test and reduced social recognition were observed, and were associated with altered BDNF/TrkB signalling, TRPV1 phosphorylation and neuronal firing in the hippocampus. Moreover, morphological rearrangements of non-neuronal cells in brain areas controlling emotional behaviour were detected. Subsequent probiotic administration, compared with vehicle, counteracted most of these gut inflammatory, behavioural, biochemical and functional alterations. Interestingly, levels of Lachnospiraceae were found to significantly correlate with the behavioural changes observed in dysbiotic mice. Our findings clarify some of the biomolecular and functional modifications leading to the development of affective disorders associated with gut microbiota alterations.

Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor.

The endogenous fatty acid amide palmitoylethanolamide (PEA) has been shown to exert anti-inflammatory actions mainly through inhibition of the release of pro-inflammatory molecules from mast cells, monocytes and macrophages. Indirect activation of the endocannabinoid (eCB) system is among the several mechanisms of action that have been proposed to underlie the different effects of PEA in vivo. In this study, we used cultured rat microglia and human macrophages to evaluate whether PEA affects eCB signaling. PEA was found to increase CB2 mRNA and protein expression through peroxisome proliferator-activated receptor-α (PPAR-α) activation. This novel gene regulation mechanism was demonstrated through: (i) pharmacological PPAR-α manipulation, (ii) PPAR-α mRNA silencing, (iii) chromatin immunoprecipitation. Moreover, exposure to PEA induced morphological changes associated with a reactive microglial phenotype, including increased phagocytosis and migratory activity. Our findings suggest indirect regulation of microglial CB2R expression as a new possible mechanism underlying the effects of PEA. PEA can be explored as a useful tool for preventing/treating the symptoms associated with neuroinflammation in CNS disorders.

Predictive factors of difficult procedure in octogenarians undergoing elective laparoscopic cholecystectomy: a single center experience.

AIM: To assess the feasibility and safety of laparoscopic cholecystectomy (LC) in very elderly patients with particular attention to the predicitive factors of difficulty. PATIENTS AND METHODS: All patients aged ≥ 80 undergoing elective LC for lithiasis at our institution since 1st January 2015 to 31st December 2015 were included in the study. Exclusion criteria were: a) acute cholecystitis; b) biliary pancreatitis; c) biliary tract neoplasms; d) urgent procedure. Pre-, intra- and postoperative data were recorded. RESULTS: During the study period, we performed 72 LC and we enrolled 17 patients aged ≥ 80 with a M:F = 5:12. Of these, 10 patients had a "difficult" cholecystectomy. In seven cases an intraoperative cholangiography (IOC) was performed. Postoperative course was regular but in two patients we had an Oddian spasm in 1st postoperative day. Female sex (p=0.03) and preoperative high level of serum amylase (p= 0.02) were significantly associated to difficult cholecystectomy in elderly patients. CONCLUSION: LC in octogenarians is feasible and safe. However, sex and serum amylase can help the surgeon to predict a more difficult procedure in elective LC. In this group of patients an approach based on the individual risk is desirable and the patient could be referred to a multidisciplinary approach.

Laparoscopic or open hemicolectomy for elderly patients with right colon cancer? A retrospective analysis.

AIM: The aim of this study was to compare the short-term surgical outcomes of laparoscopically-assisted right hemicolectomy (LRH) and open right hemicolectomy (ORH) in elderly patients. Patients and methods-Results. Seventy-five patients underwent right hemicolectomy for cancer during the study period, with 41 patients aged ≥ 70 years old. Twenty-four patients underwent ORH and seventeen patients had a LRH (58% vs 42%).We found no differences between ORH and LRH in terms of mean operative time :89,5 minutes in open vs 80 minutes in laparoscopic group and return of bowel function (2,76 vs 2,54 days). Also the length of hospital stay did not differ significantly between the two groups (8,5 days in ORH vs 7 days in LRH - p 0,06). Postoperative morbidity was higher in ORH (25% vs 5%) though not statistically significant and the incidence of anastomotic leakage was similar between the two groups (8% vs 5%). CONCLUSION: Laparoscopic RH in an elderly population is feasible and safe. However, we found no evidence to suggest that it is better than open RH and think that the decision regarding the method of operation should reflect surgeon expertise, patient co-morbidities and the necessity to perform extended resections.

Multi-organ resection for locally advanced adrenocortical cancer: surgical strategy and literature review.

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with an estimated worldwide incidence of 0.5-2 per million/year. Complete surgical removal of ACC represents the current treatment of choice for this tumor. A disease-free resection margin (R0) is an important predictor of long-term survival: surgery is demanding and must be performed by a highly experienced surgical team. We report the surgical strategy adopted in a patient with locally advanced ACC and virilization to obtain a R0 resection.

Palmitoylethanolamide reduces pain-related behaviors and restores glutamatergic synapses homeostasis in the medial prefrontal cortex of neuropathic mice.

BACKGROUND: Enhanced supraspinal glutamate levels following nerve injury are associated with pathophysiological mechanisms responsible for neuropathic pain. Chronic pain can interfere with specific brain areas involved in glutamate-dependent neuropsychological processes, such as cognition, memory, and decision-making. The medial prefrontal cortex (mPFC) is thought to play a critical role in pain-related depression and anxiety, which are frequent co-morbidities of chronic pain. Using an animal model of spared nerve injury (SNI) of the sciatic nerve, we assess bio-molecular modifications in glutamatergic synapses in the mPFC that underlie neuropathic pain-induced plastic changes at 30 days post-surgery. Moreover, we examine the effects of palmitoylethanolamide (PEA) administration on pain-related behaviours, as well as the cortical biochemical and morphological changes that occur in SNI animals. RESULTS: At 1 month, SNI was associated with mechanical and thermal hypersensitivity, as well as depression-like behaviour, cognitive impairments, and obsessive-compulsive activities. Moreover, we observed an overall glutamate synapse modification in the mPFC, characterized by changes in synaptic density proteins and amino acid levels. Finally, with regard to the resolution of pain and depressive-like syndrome in SNI mice, PEA restored the glutamatergic synapse proteins and changes in amino acid release. CONCLUSIONS: Given the potential role of the mPFC in pain mechanisms, our findings may provide novel insights into neuropathic pain forebrain processes and indicate PEA as a new pharmacological tool to treat neuropathic pain and the related negative affective states. Graphical Abstract Palmitoylethanolamide: a new pharmacological tool to treat neuropathic pain and the related negative affective states.

PC1, a non-peptide PKR1-preferring antagonist, reduces pain behavior and spinal neuronal sensitization in neuropathic mice.

Peripheral neuropathy is characterized by abnormal pain responses triggered by the release of several mediators and neuronal hyperexcitability at the spinal cord level. Emerging evidence indicates that the enhanced activity of dorsal horn neurons requires communication with glia and microglia, cells that are physiologically involved in neuronal wellbeing. Prokineticins (PKs), which include PK1 and PK2, represent a novel family of chemokines characterized by a unique structural motif comprising five disulfide bonds. They are expressed in the peripheral and central nervous system. PKs bind two G protein coupled receptors, PKR1 and PKR2, and participate in the regulation of several biological processes, including pain sensation. This study aimed to investigate the anti-nociceptive effect of PC1, a non-peptide PKR1-preferring antagonist, in a mouse model of neuropathic pain. To do this, we assessed the activity of spinal cord nociceptive neurons as well as astrocyte and microglia phenotypes after repeated administration of PC1 in vivo. PC1 treatment strongly delayed the development of thermal hyperalgesia and tactile and mechanical allodynia. It also reduced spinal microglial and glial activation 8 days post injury in spared nerve injury (SNI) mice. Neuropathic mice showed an increased level of PK2 protein in the spinal cord, mostly in astrocytes. PC1 treatment completely reversed the increased responsiveness to mechanical stimuli, the decreased threshold of neuronal activation, and the increased spontaneous activity that were observed in nociceptive specific (NS) neurons of SNI mice.

Heavy smoking and lung cancer: are women at higher risk? Result of the ICARE study.

BACKGROUND: Whether women are more or equally susceptible to the carcinogenic effects of cigarette smoke on the lungs compared with men is a matter of controversy. Using a large French population-based case-control study, we compared the lung cancer risk associated with cigarette smoking by gender. METHODS: The study included 2276 male and 650 female cases and 2780 male and 775 female controls. Lifetime smoking exposure was represented by the comprehensive smoking index (CSI), which combines the duration, intensity and time since cessation of smoking habits. The analysis was conducted among the ever smokers. All of the models were adjusted for age, department (a regional administrative unit), education and occupational exposures. RESULTS: Overall, we found that the lung cancer risk was similar among men and women. However, we found that women had a two-fold greater risk associated with a one-unit increase in CSI than men of developing either small cell carcinoma (OR=15.9, 95% confidence interval (95% CI) 7.6, 33.3 and 6.6, 95% CI 5.1, 8.5, respectively; P<0.05) or squamous cell carcinoma (OR=13.1, 95% CI 6.3, 27.3 and 6.1, 95% CI 5.0, 7.3, respectively; P<0.05). The association was similar between men and women for adenocarcinoma. CONCLUSION: Our findings suggest that heavy smoking might confer to women a higher risk of lung cancer as compared with men.

The A1 adenosine receptor as a new player in microglia physiology.

The purinergic system is highly involved in the regulation of microglial physiological processes. In addition to the accepted roles for the P2 X4,7 and P2 Y12 receptors activated by adenosine triphosphate (ATP) and adenosine diphosphate, respectively, recent evidence suggests a role for the adenosine A2A receptor in microglial cytoskeletal rearrangements. However, the expression and function of adenosine A1 receptor (A1AR) in microglia is still unclear. Several reports have demonstrated possible expression of A1AR in microglia, but a new study has refuted such evidence. In this study, we investigated the presence and function of A1AR in microglia using biomolecular techniques, live microscopy, live calcium imaging, and in vivo electrophysiological approaches. The aim of this study was to clarify the expression of A1AR in microglia and to highlight its possible roles. We found that microglia express A1AR and that it is highly upregulated upon ATP treatment. Moreover, we observed that selective stimulation of A1AR inhibits the morphological activation of microglia, possibly by suppressing the Ca(2+) influx induced by ATP treatment. Finally, we recorded the spontaneous and evoked activity of spinal nociceptive-specific neuron before and after application of resting or ATP-treated microglia, with or without preincubation with a selective A1AR agonist. We found that the microglial cells, pretreated with the A1AR agonist, exhibit lower capability to facilitate the nociceptive neurons, as compared with the cells treated with ATP alone.

The genetic ablation or pharmacological inhibition of TRPV1 signalling is beneficial for the restoration of quiescent osteoclast activity in ovariectomized mice.

BACKGROUND AND PURPOSE: Osteoporosis is a condition characterized by a decrease in bone density, which decreases its strength and results in fragile bones. The endocannabinoid/endovanilloid system has been shown to be involved in the regulation of skeletal remodelling. The aim of this study was to investigate the possible modulation of bone mass mediated by the transient receptor potential vanilloid type 1 channel (TRPV1) in vivo and in vitro. EXPERIMENTAL APPROACH: A multidisciplinary approach, including biomolecular, biochemical and morphological analysis, was used to investigate the involvement of TRPV1 in changes in bone density in vivo and osteoclast activity in vitro, in wild-type and Trpv1(-/-) mice, that had undergone ovariectomy or had a sham operation. KEY RESULTS: Genetic deletion of Trpv1 as well as pharmacological inhibition/desensitization of TRPV1 signalling dramatically reduced the osteoclast activity in vitro and prevented the ovariectomy-induced bone loss in vivo, whereas the expression of cannabinoid type 2 (CB2 ) receptors was increased. CONCLUSIONS AND IMPLICATIONS: These findings highlight the pivotal role TRPV1 channels play in bone resorption and suggest a possible cross-talk between TRPV1 and CB2 receptors. Based on these results, hybrid compounds acting on both TRPV1 and CB2 receptors in an opposite manner could provide a future pharmacological tool for the treatment of diseases associated with disturbances in the bone remodelling process.

Pharmacological activity of a Bv8 analogue modified in position 24.

BACKGROUND AND PURPOSE: The amphibian peptide Bv8 induces potent nociceptive sensitization in rodents. Its mammalian homologue, prokineticin 2 (PROK2), is strongly up-regulated in inflamed tissues and is a major determinant in triggering inflammatory pain. Bv8 and PROK2 activate two closely related GPCRs, PK(1) and PK(2) , in a relatively non-selective fashion. To characterize better the roles of the two receptors in hyperalgesia and to obtain ligands whose binding affinity and efficacy differed for the two receptors, we modified the Bv8 molecule in regions essential for receptor recognition and activation. EXPERIMENTAL APPROACH: We modified the Bv8 molecule by substituting Trp in position 24 with Ala (A-24) and compared it with Bv8 for binding and activating PK(1) and PK(2) receptors in cell preparations and in affecting nociceptive thresholds in rodents. KEY RESULTS: A-24 preferentially bound to PK(2) receptors and activated them with a lower potency (5-fold) than Bv8. When systemically injected, A-24 induced Bv8-like hyperalgesia in rats and in mice, at doses 100 times higher than Bv8. Locally and systemically injected at inactive doses, A-24 antagonized Bv8-induced hyperalgesia. In rat and mouse models of inflammatory and post-surgical pain, A-24 showed potent and long-lasting anti-hyperalgesic activity. Unlike Bv8, A-24 increased ß-endorphin levels in mouse brain. CONCLUSIONS AND IMPLICATIONS: A-24 induced its anti-hyperalgesic effect in rodents by directly blocking nociceptor PK(1) receptors and by activating the central opioid system and the descending pain control pathway through brain PK(2) receptors.

Antibacterial and anti-biofilm effects of cathelicidin peptides against pathogens isolated from cystic fibrosis patients.

Six different cathelicidin-derived peptides were compared to tobramycin for antibacterial and anti-biofilm effects against S. aureus, P. aeruginosa, and S. maltophilia strains isolated from cystic fibrosis patients. Overall, SMAP-29, BMAP-28, and BMAP-27 showed relevant antibacterial activity (MIC(50) 4-8µg/ml), and in some cases higher than tobramycin. In contrast, indolicidin, LL-37, and Bac7(1-35) showed no significant antimicrobial activity (MIC(50)>32µg/ml). Killing kinetics experiments showed that in contrast to tobramycin the active cathelicidin peptides exert a rapid bactericidal activity regardless of the species tested. All three peptides significantly reduced biofilm formation by S. maltophilia and P. aeruginosa strains at 1/2× MIC, although at a lower extent than tobramycin. In addition, BMAP-28, as well as tobramycin, was also active against S. aureus biofilm formation. Preformed biofilms were significantly affected by bactericidal SMAP-29, BMAP-27 and BMAP-28 concentrations, although at a lesser extent than tobramycin. Overall, our results indicate the potential of some cathelicidin-derived peptides for the development of novel therapeutic agents for cystic fibrosis lung disease.