Calcitonin gene-related peptide (CGRP), the most abundant neuropeptide in primary afferent sensory neurons, is strongly implicated pathophysiology of migraine headache, but its role still equivocal. As a new approach to treatment, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs) were developed reduce availability CGRP, and found effective reducing frequency chronic episodic migraine. We recently tested effect fremanezumab (TEV-48125), CGRP-mAb, on activity second-order trigeminovascular...

A large body of evidence supports an important role for calcitonin gene-related peptide (CGRP) in migraine pathophysiology. This gave rise to a global effort develop new generation therapeutics that inhibit the interaction CGRP with its receptor migraineurs. Recently, class such drugs, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs), were found be effective reducing frequency migraine. The purpose this study was better understand how CGRP-mAb fremanezumab (TEV-48125) modulates...

Acute and persistent post-traumatic headache are often debilitating consequences of traumatic brain injury. Underlying physiological mechanisms its persistence remain unknown, there currently no approved therapies for these conditions. Post-traumatic presents with a migraine-like phenotype. As calcitonin-gene related peptide promotes migraine headache, we explored the efficacy timing intervention an anti- monoclonal antibody in novel preclinical models acute following mild injury event...

The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed key role this axis in pathogenesis. Three antibodies against CGRP - fremanezumab, galcanezumab and eptinezumab one antibody receptor, erenumab, are clinically approved therapeutics for prevention migraine. In addition, two small molecule receptor antagonists, ubrogepant rimegepant, acute treatment. Targeting either ligand or is efficacious treatment; however,...

Background The presence of calcitonin gene-related peptide and its receptors in multiple brain areas peripheral tissues previously implicated migraine initiation many associated symptoms raises the possibility that humanized monoclonal anti-calcitonin antibodies (CGRP-mAbs) can prevent by modulating neuronal behavior inside outside brain. Critical to our ability conduct a fair discussion over mechanisms action CGRP-mAbs prevention is data generation determines which possible central sites...

Objective The objective of this study was the determination role calcitonin gene-related peptide (CGRP) in induction medication overuse headache (MOH)-related migraine an injury-free preclinical model. Methods Rats were primed by a 7-day period exposure to acute therapies including sumatriptan and morphine. After additional 14-day drug-free period, rats exposed putative triggers bright light stress (BLS) or nitric oxide (NO) donor presence absence TEV48125, fully humanized CGRP antibody....

Cortical spreading depression (CSD) is a wave of neuronal depolarization thought to underlie migraine aura. Calcitonin gene-related peptide (CGRP) potent vasodilator involved in pathophysiology. Evidence for functional connectivity between CSD and CGRP has triggered scientific interest the possibility that antagonism may disrupt vascular responses ensuing plasma protein extravasation (PPE). Using imaging tools allow us generate continuous, live, high-resolution views spatial temporal changes...

Abstract Migraine headache results from activation of meningeal nociceptors, however, the hypothalamus is activated many hours before emergence pain. How hypothalamic neural mechanisms may influence trigeminal nociceptor function remains unknown. Stress a common migraine trigger that engages dynorphin/kappa opioid receptor (KOR) signalling and increases circulating prolactin. Prolactin acts at both long short prolactin isoforms are expressed in afferents. Following downregulation isoform,...

Mutations in the tyrosine kinase receptor trkB or one of its natural ligands, brain-derived neurotrophic factor (BDNF), lead to severe hyperphagia and obesity rodents and/or humans. Here, we show that peripheral administration neurotrophin-4 (NT4), second ligand for trkB, suppresses appetite body weight a dose-dependent manner several murine models obesity. NT4 treatment increased lipolysis, reduced fat content leptin, elicited long-lasting amelioration hypertriglyceridemia hyperglycemia....

The blood-brain barrier (BBB) largely excludes antibodies from entering the central nervous system, thus limiting potential of therapeutic to treat conditions such as neurodegenerative diseases and neuro-psychiatric disorders. Here, we demonstrate that transport human across BBB in mice can be enhanced by modulating their interactions with neonatal Fc receptor (FcRn). When M252Y/S254T/T246E substitutions are introduced on antibody domain, immunohistochemical assays reveal widespread...

Migraine attacks are believed to originate in the brain, but exact mechanisms by which brain generates peripheral nociceptive signals that drive migraine pain remain unclear. Sensory cortex hyperexcitability has been observed consistently across different subtypes. Astrocytes detect aberrant increases cortical activity via their Gq-coupled receptors and respond releasing gliotransmitters other factors with pro-inflammatory properties. In present study, we used a rat model investigate whether...

Introduction Females are thought to have increased risk of developing post-traumatic headache following a traumatic head injury or concussion. However, the processes underlying this susceptibility remain unclear. We previously demonstrated development headache-like pain behaviors in male rat model mild closed injury, along with ability sumatriptan and an anti-calcitonin-gene-related peptide monoclonal antibody ameliorate these behaviors. Here, we conducted follow-up study explore...

Monoclonal antibodies directed against the neuropeptide calcitonin gene-related peptide (CGRP) belong to a new generation of therapeutics that are effective in prevention migraine. CGRP, potent vasodilator, is strongly implicated pathophysiology migraine, but its role remains be fully elucidated. The hemisected rat head preparation and laser Doppler flowmetry were used examine effects on CGRP release from dura mater meningeal blood flow subcutaneously injected anti-CGRP monoclonal antibody...

Fremanezumab (TEV-48125) is a fully humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) that has shown positive results in the prevention of episodic migraine and chronic migraine. Previous preclinical studies have revealed CGRP antagonistic effects on intracranial arteries (ICA). The aim study was to evaluate vitro fremanezumab human arteries. Arteries were removed conjunction with neurosurgery (cerebral, CA, middle meningeal artery, MMA, n = 7) or reconstructive...

Irritable bowel syndrome (IBS) and bladder pain syndrome/interstitial cystitis (BPS/IC) are comorbid visceral disorders seen commonly in women with unknown etiology limited treatment options can involve organ cross-sensitization. Calcitonin gene-related peptide (CGRP) is a mediator of nociceptive processing may serve as target for therapy. In three rodent models, we employed monoclonal anti-CGRP F(ab')2 to investigate the hypothesis that cross-sensitization mediated by abnormal CGRP...

Loss of function mutations in the receptor tyrosine kinase TrkB pathway resulted hyperphagia and morbid obesity human rodents. Conversely, peripheral or central stimulation by its natural ligands BDNF NT4 reduced body weight food intake mice, supporting idea that is a key anorexigenic signal downstream melanocortin-4 (Mc4r) system. Here we show non-human primates agonists were when applied centrally, but surprisingly orexigenic, leading to gain appetite, weight, fat deposits serum leptin...

Abstract Most centrally acting migraine preventive drugs suppress frequency and velocity of cortical spreading depression (CSD). The purpose the current study was to determine how new class peripherally drug (ie, anti-CGRP-mAbs) affect CSD—an established animal model aura, which affects about 1/3 people with migraine—when allowed cross blood–brain barrier (BBB). Using standard electrocorticogram recording techniques rats in BBB intentionally compromised, we found that when opened,...

Urokinase receptor antagonists based on the growth factor domains of both human and murine urokinase which show sub‐nanomolar affinities for their homologous receptors have been expressed as recombinant proteins. Further modification these molecules by preparing fusions with constant region IgG has led to high long in vivo half‐lives. Smaller peptidic inhibitors obtained a combination bacteriophage display peptide analog synthesis. All inhibit binding domain uPA enhance vitronectin. Protein...

Irritable bowel syndrome (IBS) is a brain-gut disorder characterized by abdominal pain and altered habits. Although the etiology of IBS remains unclear, stress in adulthood or early life has been shown to be significant factor development symptomatology. Evidence suggests that aberrant calcitonin gene-related peptide (CGRP) signaling may involved afferent sensitization visceral organ hypersensitivity. Here, we used monoclonal anti-CGRP divalent antigen-binding fragment [F(ab′)₂]...

The metabolic enzyme transketolase (TK) plays a crucial role in tumor cell nucleic acid synthesis, using glucose through the elevated nonoxidative pentose phosphate pathway (PPP). Identification of inhibitors specifically targeting TK and preventing PPP from generating RNA ribose precursor, ribose-5-phosphate, provides novel approach for developing effective anticancer therapeutic agents. full-length human gene was cloned expressed Escherichia coli recombinant protein purified to...

Migraine pain is frequently accompanied by cranial hyperalgesia and allodynia. Calcitonin gene-related peptide (CGRP) implicated in migraine pathophysiology but its role facial hypersensitivity not entirely clear. In this study, we investigated if the anti-CGRP monoclonal antibody fremanezumab, which therapeutically used chronic episodic migraines, can modify sensitivity recorded a semi-automatic system. Rats of both sexes primed to drink from sweet source had pass noxious mechanical or heat...

The low-barrier hydrogen bond (LBHB) between the Asp and His residues of catalytic triad in a serine protease was perturbed via D32C mutation subtilisin BPN' (Bacillus N'). This mutant enzyme catalyzes hydrolysis N-Suc-Ala-Ala-Pro-Phe-SBzl with kcat/Km value that is only 8-fold reduced from wild-type (WT) enzyme. for corresponding p-nitroanilide (pNA) substrate 50-fold lower than WT (ΔΔG⧧ = 2.2 kcal/mol). pKa controlling ascending limb pH versus profile lowered 7.01 to 6.53 (D32C), implying...