Effects of Incretin Pathway Elements on Bone Properties.

Introduction The effects of incretin-based drugs, such as receptor agonists of glucagon-like peptide-1 and inhibitors of dipeptidyl peptidase-4, on bone metabolism are not completely clear yet. The aim of this study is to compare the effects of glucagon-like peptide-1 and inhibitors of dipeptidyl peptidase-4 on the bone to see how different elements of the incretin pathway affect bone quality in terms of biomechanical properties, bone turnover, and mineral properties. Materials and methods Forty 10-week-old Wistar rats were divided into four groups: a control group, a control diabetic group, a diabetic group treated with sitagliptin, and a diabetic group treated with exenatide. Type 2 diabetes was simulated by dietary manipulation in addition to low-dose streptozotocin, and then two different incretin-based drugs were administered. The rats were sacrificed after five weeks of therapeutic treatment. Their serum was analyzed with the enzyme-linked immunosorbent assay (ELISA) method for basic bone turnover markers, and their right femur was subjected to a three-point bending test. Finally, Hematoxylin & Eosin staining, in addition to Raman spectroscopy, were employed to access the collagen and mineral properties of the bone. Results Both incretin-based drugs reduced osteoclast function; however, they were not able to restore osteoblastic function to normal. The net effect on bone strength was surprising: bone elasticity was restored by the antidiabetic treatment, but bone strength deteriorated. Exenatide had a slightly more pronounced effect, which, although not significant, points to the direction that dipeptidyl peptidase-4 (DPP4) may be a linking factor between reduced osteoclastic function and reduced bone formation, as suggested by the literature. Conclusion DPP4 receptors seem to be one of the links between reduced osteoclast function and reduced bone remodeling, so DPP4 inhibition can be more detrimental to the bone than glucagon-like peptide-1 (GLP-1) receptor agonists.

URB597 induces subtle changes to aggression in adult Lister Hooded rats.

The endocannabinoid system has been implicated in both social and cognitive processing. The endocannabinoid metabolism inhibitor, URB597, dose-dependently improves non-social memory in adult Wistar and Sprague Dawley rats, whereas its effect on social interaction (SI) is affected by both rat strain and drug dose. Lister Hooded rats consistently respond differently to drug treatment in general compared with albino strains. This study sought to investigate the effects of different doses of URB597 on social and non-social memory in Lister Hooded rats, as well as analyzing the behavioral composition of the SI. Males were tested for novel object recognition (NOR), social preference (between an object and an unfamiliar rat), social novelty recognition (for a familiar vs. unfamiliar rat) and SI with an unfamiliar rat. URB597 (0.1 or 0.3 mg/kg) or vehicle was given 30 min before testing. During SI testing, total interaction time was assessed along with time spent on aggressive and explorative behaviors. Lister Hooded rats displayed expected non-social and social memory and social preference, which was not affected by URB597. During SI, URB597 did not affect total interaction time. However, the high dose increased aggression, compared to vehicle, and decreased anogenital sniffing, compared to the low dose of URB597. In summary, URB597 did not affect NOR, social preference or social recognition memory but did have subtle behavioral effects during SI in Lister hooded rats. Based on our findings we argue for the importance of considering strain as well as the detailed composition of behavior when investigating drug effects on social behavior.

Cannabidiol Prevents Spontaneous Fear Recovery after Extinction and Ameliorates Stress-Induced Extinction Resistance.

Cannabidiol, the main non-psychotropic constituent of cannabis, has potential as a treatment for anxiety-related disorders since it reduces learned fear expression and enhances fear extinction. The return of fear over time after successful extinction and stress-induced extinction resistance are potential barriers to the treatment of these disorders with extinction-based psychological therapy. In two experiments using rats subjected to auditory fear conditioning, we determined the effects of systemic cannabidiol treatment on (1) delayed extinction and later spontaneous fear recovery, and (2) extinction resistance caused by immediate extinction (the immediate extinction deficit (IED)). In Experiment 1, cannabidiol was given before delayed extinction occurring 24 h after conditioning, with extinction recall and spontaneous fear recovery tested drug-free 1 and 21 days after extinction, respectively. We found that cannabidiol had no effect on extinction recall but it prevented spontaneous fear recovery. In Experiment 2, the IED procedure was first validated, with immediate extinction occurring 30 min after conditioning. We confirmed that immediate extinction impaired extinction recall, compared to delayed extinction. Next, cannabidiol was given before immediate or no extinction, with extinction recall tested drug-free the next day. We found that cannabidiol rescued the IED, which did not involve effects on fear memory consolidation. In summary, cannabidiol prevented spontaneous fear recovery after delayed extinction and ameliorated extinction resistance caused by immediate extinction. Although the pharmacological mechanisms underlying these effects remain to be determined, our results add to evidence indicating that cannabidiol might prove useful as an adjunct for potentiating the psychological treatment of anxiety-related disorders.

In it together? The case for endocannabinoid-noradrenergic interactions in fear extinction.

Anxiety and trauma-related disorders, such as post-traumatic stress disorder (PTSD), are debilitating mental illnesses with great personal and socioeconomic costs. Examining memory formation and relevant behavioural responding associated with aversive stimuli may improve our understanding of the neurobiology underlying fear memory processing and PTSD treatment. The neurocircuitry underpinning learned fear and its inhibition through extinction is complex, involving synergistic interactions between different neurotransmitter systems in inter-connected brain areas. Endocannabinoid and noradrenergic transmission have both been implicated separately in fear memory processing and PTSD, but potential interactions between these systems in relation to fear extinction have received little attention to date. Their receptors are expressed together in brain areas crucial for fear extinction, which is enhanced by both cannabinoid and noradrenergic receptor activation in these areas. Moreover, cannabinoid signalling modulates the activity of locus coeruleus noradrenaline (NA) neurons and the release of NA in the medial prefrontal cortex, a brain area that is crucial for fear extinction. Interestingly, endocannabinoid-noradrenergic system interactions have been shown to regulate the encoding and retrieval of fear memory. Thus, noradrenergic regulation of fear extinction may also be driven indirectly in part via cannabinoid receptor signalling. In this perspective paper, we collate the available relevant literature and propose a synergistic role for the endocannabinoid and noradrenergic systems in regulating fear extinction, the study of which may further our understanding of the neurobiological substrates of PTSD and its treatment.

Endocannabinoid metabolism inhibition has no effect on spontaneous fear recovery or extinction resistance in Lister hooded rats.

Endocannabinoid transmission is emerging as a target for treating anxiety-related disorders, given its regulation of fear extinction. Boosting anandamide levels via inhibition of its metabolism by fatty acid amide hydrolase (FAAH) can enhance extinction, whereas inhibiting monoacylglycerol lipase (MAGL) to elevate 2-arachidonoylglycerol levels can impair extinction. However, whether endocannabinoids regulate fear relapse over time or extinction resistance remains unclear. In two experiments using auditory fear conditioned rats, we examined the effects of the FAAH inhibitor URB597 and the MAGL inhibitor JZL184 administered systemically on 1) spontaneous fear recovery after delayed extinction, and 2) extinction resistance resulting from immediate extinction [the immediate extinction deficit (IED)]. In Experiment 1, URB597 or JZL184 was given immediately after delayed extinction occurring 24 h after conditioning. Extinction recall and spontaneous fear recovery were tested drug-free 1 and 21 days later, respectively. We found no effects of either drug on extinction recall or spontaneous fear recovery. In Experiment 2, URB597 or JZL184 was given before immediate extinction occurring 30 min after conditioning and extinction recall was tested drug-free the next day. We also examined the effects of propranolol, a beta-adrenoceptor antagonist that can rescue the IED, as a positive control. JZL184 enhanced fear expression and impaired extinction learning but we found no lasting effects of URB597 or JZL184 on cued extinction recall. Propranolol reduced fear expression but, unexpectedly, had no enduring effect on extinction recall. The results are discussed in relation to various methodological differences between previous studies examining endocannabinoid and adrenergic regulation of fear extinction.

Ameloblastoma on the Maxillary Sinus: Cause of Unilateral Nasal Obstruction.

Ameloblastoma is a rare, benign (99%) or malignant (1%) tumour, which has derived from dental mesenchyme. We present a case of a patient mainly complaining about obstruction on the right nasal cavity. Endoscopy and computed tomography revealed a soft tissue mass occupying the maxillary sinus to the middle meatus causing complete obstruction of the right nasal cavity. Endoscopic en block removal of the lesion and biopsy confirmed follicular ameloblastoma. Literature review confirms the extremely rare frequency of ameloblastoma. The aim of the present study is to expand on our knowledge of a rare pathological entity that can frequently be misdiagnosed.

Cannabinoid Regulation of Fear and Anxiety: an Update.

PURPOSE OF REVIEW: Anxiety- and trauma-related disorders are prevalent and debilitating mental illnesses associated with a significant socioeconomic burden. Current treatment approaches often have inadequate therapeutic responses, leading to symptom relapse. Here we review recent preclinical and clinical findings on the potential of cannabinoids as novel therapeutics for regulating fear and anxiety. RECENT FINDINGS: Evidence from preclinical studies has shown that the non-psychotropic phytocannabinoid cannabidiol and the endocannabinoid anandamide have acute anxiolytic effects and also regulate learned fear by dampening its expression, enhancing its extinction and disrupting its reconsolidation. The findings from the relevant clinical literature are still very preliminary but are nonetheless encouraging. Based on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future.

Spinal Accessory Nerve Duplication: A Case Report and Literature Review.

Aim of the present study is to expand our knowledge of the anatomy of the 11th cranial nerve and discuss the clinical importance and literature pertaining to accessory nerve duplication. We present one case of duplicated spinal accessory nerve in a patient undergoing neck dissection for oral cavity cancer. The literature review confirms the extremely rare diagnosis of a duplicated accessory nerve. Its clinical implication is of great importance. From this finding, a further extension to our knowledge of the existing anatomy is proposed.