Evaluation of the effect of Exercise Trainings and CGRP receptor antagonist (BIBN 4096) on mitochondrial dynamic in the hippocampus of male Wistar rats.

BACKGROUND: Exercise training showed beneficial effects on brain. The purpose of the present study is to evaluate the effect of six weeks of high-intensity interval training (HIIT) and Endurance training (ET) with calcitonin gene-related peptide (CGRP) receptor antagonist on the expression of genes involved in mitochondrial dynamics and apoptosis in hippocampal tissue of male Wistar rats. METHODS: In this study, forty-two healthymale Wistar rats (8-week) were randomly divided into 6 groups (n = 7) as follow; 1) Control; 2) HIIT which performed 6 weeks of HIIT; 3) ET which performed 6 weeks of endurance training; 4) CGRPi received 10 mg/kg CGRP receptor antagonist every day at the last 2 weeks; 5) CGRPi-HIIT performed HIIT and received CGRP receptor antagonist; 6) CGRPi-ET performed ET and received CGRP receptor antagonist. Real-time PCR (2-ΔΔCT) and western blotting were employedto measure the expression of genes and protein, respectively. RESULTS: HIIT and ET significantly increased Bcl-2, Pgc-1α, Sirt3, and Nrf-1 gene expression in the hippocampal tissue (p < 0.05, p < 0.01, p < 0.01, and p < 0.001, respectively). ET-CGRPi and HIIT-CGRPi significantly increased Sirt3, Pgc-1α, and Nrf-1 gene expression compared to the control group (p < 0.05, p < 0.01, and p < 0.05, respectively). CONCLUSION: ET and HIIT-induced physiological alterations in the hippocampus. In fact, this modulation showed protective properties in the hippocampusvia up regulation of Bcl-2, Pgc-1α, Nrf-1, and Sirt3 gene expression. CGRPi did not cause gene or protein changes harmful to mitochondrial dynamic balance and apoptosis in the hippocampus of rats.

Gαs-Coupled CGRP Receptor Signaling Axis from the Trigeminal Ganglion Neuron to Odontoblast Negatively Regulates Dentin Mineralization.

An inflammatory response following dental pulp injury and/or infection often leads to neurogenic inflammation via the axon reflex. However, the detailed mechanism underlying the occurrence of the axon reflex in the dental pulp remains unclear. We sought to examine the intracellular cyclic adenosine monophosphate (cAMP) signaling pathway in odontoblasts via the activation of Gs protein-coupled receptors and intercellular trigeminal ganglion (TG) neuron-odontoblast communication following direct mechanical stimulation of TG neurons. Odontoblasts express heterotrimeric G-protein α-subunit Gαs and calcitonin receptor-like receptors. The application of an adenylyl cyclase (AC) activator and a calcitonin gene-related peptide (CGRP) receptor agonist increased the intracellular cAMP levels ([cAMP]i) in odontoblasts, which were significantly inhibited by the selective CGRP receptor antagonist and AC inhibitor. Mechanical stimulation of the small-sized CGRP-positive but neurofilament heavy chain-negative TG neurons increased [cAMP]i in odontoblasts localized near the stimulated neuron. This increase was inhibited by the CGRP receptor antagonist. In the mineralization assay, CGRP impaired the mineralization ability of the odontoblasts, which was reversed by treatment with a CGRP receptor antagonist and AC inhibitor. CGRP establishes an axon reflex in the dental pulp via intercellular communication between TG neurons and odontoblasts. Overall, CGRP and cAMP signaling negatively regulate dentinogenesis as defensive mechanisms.

A CGRP receptor antagonist peptide formulated for nasal administration to treat migraine.

OBJECTIVES: To investigate the formulation of the peptide-based antagonist (34 Pro,35 Phe)CGRP27-37 , of the human calcitonin gene-related peptide (CGRP) receptor as a potential nasally delivered migraine treatment. METHODS: Peptide sequences were prepared using automated methods and purified by preparative HPLC. Their structure and stability were determined by LC-MS. Antagonist potency was assessed by measuring CGRP-stimulated cAMP accumulation in SK-N-MC, cells and in CHO cells overexpressing the human CGRP receptor. In vivo activity was tested in plasma protein extravasation (PPE) studies using Evans blue dye accumulation. Peptide-containing chitosan microparticles were prepared by spray drying. KEY FINDINGS: (34 Pro,35 Phe)CGRP27-37 exhibited a 10-fold increased affinity compared to αCGRP27-37 . Administration of (34 Pro,35 Phe)CGRP27-37 to mice led to a significant decrease in CGRP-induced PPE confirming antagonistic properties in vivo. There was no degradation of (34 Pro,35 Phe)CGRP27-37 and no loss of antagonist potency during formulation and release from chitosan microparticles. CONCLUSIONS: (34 Pro,35 Phe)CGRP27-37 is a potent CGRP receptor antagonist both in vitro and in vivo, and it can be formulated as a dry powder with no loss of activity indicating its potential as a nasally formulated anti-migraine medicine.