Dual depolarization responses generated within the same lateral septal neurons by TRPC4-containing channels

In the central nervous system, canonical transient receptor potential (TRPC) channels have been implicated in mediating neuronal excitation induced by stimulating metabotropic receptors, including group 1 metabotropic glutamate receptors (mGluRs). Lateral septal (LS) neurons express high levels of TRPC4 and group I mGluRs. However, to what extent native TRPC4-containing channels (TRPC4-cc) are activated as well as the impact of different levels of TRPC4-cc activation on neuronal excitability remain elusive. Here, we report that stimulating LS neurons with group I mGluR agonist, (S)-3,5-DHPG, causes either an immediate increase in firing rate or an initial burst followed by a pause of firing, which can be correlated with below-threshold-depolarization (BTD) or above-threshold-plateau-depolarization (ATPD), respectively, in whole-cell recordings. The early phase of BTD and the entire ATPD are completely absent in neurons from TRPC4^?/? mice. Moreover, in the same LS neurons, BTD can be converted to ATPD at more depolarized potentials or with a brief current injection, suggesting that BTD and ATPD may represent partial and full activations of TRPC4-cc, respectively. We show that coincident mGluR stimulation and depolarization is required to evoke strong TRPC4-cc current, and Na⁺ and Ca²⁺ influx, together with dynamic changes of intracellular Ca²⁺, are essential for ATPD induction. Our results suggest that TRPC4-cc integrates metabotropic receptor stimulation with intracellular Ca²⁺ signals to generate two interconvertible depolarization responses to affect excitability of LS neurons in distinct fashions.     

Behavioral effects of the novel cannabinoid full agonist AM 411

AM 411 ((-)-1-adamantyl-Delta8-tetrahydrocannabinol) is a novel full agonist at cannabinoid CB1 receptors. The present studies were conducted to provide behavioral characterization of this compound in rats. It was hypothesized that AM 411 should produce behavioral effects similar to known cannabinoid agonists, and that these effects should be inhibited by co-treatment with a CB1 antagonist. In Experiments 1 and 2, AM 411 dose-dependently produced behaviors consistent with CB1 agonism, including analgesia, hypothermia, catalepsy and reductions in locomotion, which were blocked by a CB1-selective antagonist. In Experiment 3, AM 411 produced a dose-dependent suppression of lever-pressing on a fixed-ratio 5 (FR5) schedule, a task known to be sensitive to administration of CB1 agonists. Detailed analysis of the temporal patterns of operant responding showed that AM 411 altered the distribution of interresponse times. Experiment 4 showed that AM 411 decreased relative interior activity in the open field, which is suggestive of an anxiogenic effect. It is concluded that AM 411 produces CB1 agonist-like behavior with potency between that of WIN 55,212-2 and AM 356. AM 411 could be a useful tool for understanding the behavioral and neural effects of CB1 receptor stimulation.     

Adamantyl cannabinoids: a novel class of cannabinergic ligands

Structure-activity relationship studies have established that the aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids. We have now synthesized a series of analogues in which a variety of adamantyl substituents were introduced at the C3 position of Delta(8)-THC. Our lead compound, (-)-3-(1-adamantyl)-Delta(8)-tetrahydrocannabinol (1a, AM411), was found to have robust affinity and selectivity for the CB1 receptor as well as high in vivo potency. The X-ray crystal structure of 1a was determined. Exploration of the side chain conformational space using molecular modeling approaches has allowed us to develop cannabinoid side chain pharmacophore models for the CB1 and CB2 receptors. Our results suggest that although a bulky group at the C3 position of classical cannabinoids could be tolerated by both CB1 and CB2 binding sites, the relative orientation of that group with respect to the tricyclic component can lead to receptor subtype selectivity.     

Rehabilitation of a missing ear with an implant retained auricular prosthesis

Burns can leave a patient with a severely debilitating disability even after treatment. The objectives of burn rehabilitation are to minimize the adverse effects caused by the injury while rehabilitating the patient''s physical and psychological well-being, maximizing social integration. Long-term success of maxillofacial prostheses mainly depends on the retention. Extra oral implant retained prostheses have proved to be a predictable treatment option for maxillofacial rehabilitation. Replacement of a severely deformed external ear with burned tissues may be satisfactorily accomplished by a cosmetic prosthesis anchored by implants integrated in the skull. The use of such implants is now a well-recognized method for creating a stable result in maxillofacial rehabilitation. This case report describes a safe, simple and economical method for the rehabilitation of a patient with missing right auricle using an implant supported silicone prosthesis. The implant was placed in the mastoid region of the temporal bone. Reconstruction of the ear was done with auricular silicone prosthesis, retained using magnets incorporated in an autopolymerizing resin shim to decrease the weight of the prosthesis on a single implant. This method eliminates the need of tedious laboratory procedures and exact casting and fitting requirements of a metal substructure while minimizing the overall weight and cost of the prosthesis while maintaining adequate support, esthetics and retention of the prosthesis.     

Bispecific antibody based therapeutics: Strengths and challenges

Monoclonal antibody-based targeted therapy has greatly improved treatment options for patients. However, long-term efficacy of such antibodies is limited by resistance mechanisms. New insights into the mechanisms by which tumors evade immune control have driven innovative therapeutic strategies to eliminate cancer by re-directing immune cells to tumors. Advances in protein engineering technology have generated multiple bispecific antibody (BsAb) formats capable of targeting multiple antigens as a single agent. Approval of two BsAb and three check point blocking mAbs represent a paradigm shift in the use of antibody constructs. Since BsAbs can directly target immune cells to tumors, drug resistance and severe adverse effects are much reduced. The wave of next generation “bispecific or multispecific antibodies” has advanced multiple candidates into ongoing clinical trials. In this review, we focus on preclinical and clinical studies in hematological malignancies as well as discuss reasons for the limited success of BsAbs against solid tumors.