Enhanced post-traumatic headache-like behaviors and diminished contribution of peripheral CGRP in female rats following a mild closed head injury

AbstractIntroductionFemales are thought to have increased risk of developing posttraumatic headache (PTH) following a traumatic head injury, or concussion. However, the processes underlying this susceptibility remain unclear. We previously explored the development of PTH-like pain behaviors in a novel rat model of mild closed head injury, along with the ability of sumatriptan and an anti-calcitonin-gene-related peptide monoclonal antibody to ameliorate these behaviors. Here, we explored the development of PTH-like behaviors and the effectiveness of these headache therapies in females subjected to the same head trauma protocol.MethodsAdult female Sprague Dawley rats were subjected to a mild closed head injury using a weight-drop device. Characterization of headache and pain related behaviors included assessment of changes in cutaneous cephalic and extracephalic tactile pain sensitivity, using von Frey monofilaments. Sensitivity to headache/migraine triggers was tested by examining the effect of systemic administration of a low-dose of glyceryl trinitrate (GTN). Treatments included acute systemic administration of sumatriptan and repeated systemic administration of a mouse anti-calcitonin-gene-related peptide monoclonal antibody. Serum levels of calcitonin-gene-related peptide were measured at various time points in females and males after the head injury.ResultsFemale rats subjected to a mild closed head injury developed cutaneous mechanical hyperalgesia, that was limited to the cephalic region, and was resolved 4 weeks later. Cephalic pain hypersensitivity was ameliorated by treatment with sumatriptan, but was resistant to an early and prolonged treatment with the anti-CGRP monoclonal antibody. Following the resolution of the head injury-evoked cephalic hypersensitivity, administration of GTN produced a renewed and pronounced cephalic and extracephalic pain hypersensitivity that was inhibited by sumatriptan, but only partially by the anti-CGRP treatment. CGRP serum levels were elevated in females but not in males at 7 days post head injury.ConclusionsDevelopment of PTH-like pain behaviors following a mild closed head injury, and responsiveness to treatment in rats is sexually dimorphic. When compared to males, female rats display a prolonged state of cephalic hyperalgesia, increased responsiveness to a headache trigger, and a poorer effectiveness of an early and prolonged anti-CGRP treatment. The increased risk of females to develop PTH may be linked to enhanced responsiveness of peripheral and/or central pain pathways and a mechanism independent of peripheral CGRP signaling.

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Enhanced post-traumatic headache-like behaviors and diminished contribution of peripheral CGRP in female rats following a mild closed head injury

Cephalalgia ◽

10.1177/0333102420907597 ◽

2020 ◽

Vol 40 (7) ◽

pp. 748-760 ◽

Cited By ~ 5

Author(s):

Dara Bree ◽

Kimberly Mackenzie ◽

Jennifer Stratton ◽

Dan Levy

Keyword(s):

Monoclonal Antibody ◽

Head Injury ◽

Closed Head Injury ◽

Calcitonin Gene Related Peptide ◽

Female Rats ◽

Related Peptide ◽

Increased Risk ◽

Calcitonin Gene ◽

Closed Head ◽

Post Traumatic

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 the development of post-traumatic headache-like pain behaviors in a male rat model of mild closed head injury, along with the ability of sumatriptan and an anti-calcitonin-gene-related peptide monoclonal antibody to ameliorate these behaviors. Here, we conducted a follow-up study to explore the development of post-traumatic headache-like behaviors and the effectiveness of these headache therapies in females subjected to the same head trauma protocol. Methods Adult female Sprague Dawley rats were subjected to a mild closed head injury using a weight-drop device (n = 126), or to a sham procedure (n = 28). Characterization of headache and pain related behaviors included assessment of changes in cutaneous cephalic and extracephalic tactile pain sensitivity, using von Frey monofilaments. Sensitivity to headache/migraine triggers was tested by examining the effect of intraperitoneal administration of a low dose of glyceryl trinitrate (100 µg/kg). Treatments included acute systemic administration of sumatriptan (1 mg/kg) and repeated systemic administration of a mouse anti-calcitonin gene-related peptide monoclonal antibody (30 mg/kg). Serum levels of calcitonin gene-related peptide were measured at baseline and at various time points post head injury in new cohorts of females (n = 38) and males (n = 36). Results Female rats subjected to a mild closed head injury developed cutaneous mechanical hyperalgesia, which was limited to the cephalic region and was resolved 4 weeks later. Cephalic pain hypersensitivity was ameliorated by treatment with sumatriptan but was resistant to an early and prolonged treatment with the anti-calcitonin gene-related peptide monoclonal antibody. Following the resolution of the head injury-evoked cephalic hypersensitivity, administration of glyceryl trinitrate produced a renewed and pronounced cephalic and extracephalic pain hypersensitivity that was inhibited by sumatriptan, but only partially by the anti-calcitonin gene-related peptide treatment. Calcitonin gene-related peptide serum levels were elevated in females but not in males at 7 days post head injury. Conclusions Development of post-traumatic headache-like pain behaviors following a mild closed head injury, and responsiveness to treatment in rats is sexually dimorphic. When compared to the data obtained from male rats in the previous study, female rats display a prolonged state of cephalic hyperalgesia, increased responsiveness to a headache trigger, and a poorer effectiveness of an early and prolonged anti-calcitonin gene-related peptide treatment. The increased risk of females to develop post-traumatic headache may be linked to enhanced responsiveness of peripheral and/or central pain pathways and a mechanism independent of peripheral calcitonin gene-related peptide signaling.

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Increased severity of closed head injury or repetitive subconcussive head impacts enhances post-traumatic headache-like behaviors in a rat model

Cephalalgia ◽

10.1177/0333102420937664 ◽

2020 ◽

Vol 40 (11) ◽

pp. 1224-1239

Author(s):

Dara Bree ◽

Jennifer Stratton ◽

Dan Levy

Keyword(s):

Head Injury ◽

Closed Head Injury ◽

Calcitonin Gene Related Peptide ◽

Posttraumatic Headache ◽

Pain Hypersensitivity ◽

Head Impacts ◽

Related Peptide ◽

Calcitonin Gene ◽

Closed Head ◽

Weight Drop

Introduction Posttraumatic headache is one of the most common, debilitating, and difficult symptoms to manage after a traumatic head injury. The development of novel therapeutic approaches is nevertheless hampered by the paucity of preclinical models and poor understanding of the mechanisms underlying posttraumatic headache. To address these shortcomings, we previously characterized the development of posttraumatic headache-like pain behaviors in rats subjected to a single mild closed head injury using a 250 g weight drop. Here, we conducted a follow-up study to further extend the preclinical research toolbox for studying posttraumatic headache by exploring the development of headache-like pain behaviors in male rats subjected to a single, but more severe head trauma (450 g) as well as following repetitive, subconcussive head impacts (150 g). In addition, we tested whether these behaviors involve peripheral calcitonin gene-related peptide signaling by testing the effect of systemic treatment with an anti-calcitonin gene-related peptide monoclonal antibody (anti-calcitonin gene-related peptide mAb). Methods Adult male Sprague Dawley rats (total n = 138) were subjected to diffuse closed head injury using a weight-drop device, or a sham procedure. Three injury paradigms were employed: A single hit, using 450 g or 150 g weight drop, and three successive 150 g weight drop events conducted 72 hours apart. Changes in open field activity and development of cephalic and extracephalic tactile pain hypersensitivity were assessed up to 42 days post head trauma. Systemic administration of the anti-calcitonin gene-related peptide mAb or its control IgG (30 mg/kg) began immediately after the 450 g injury or the third 150 g weight drop with additional doses given every 6 days subsequently. Results Rats subjected to 450 g closed head injury displayed an acute decrease in rearing and increased thigmotaxis, together with cephalic tactile pain hypersensitivity that resolved by 6 weeks post-injury. Injured animals also displayed delayed and prolonged extracephalic tactile pain hypersensitivity that remained present at 6 weeks post-injury. Repetitive subconcussive head impacts using the 150 g weight drop, but not a single event, led to decreased vertical rearing as well as cephalic and extracephalic tactile pain hypersensitivity that resolved by 6 weeks post-injury. Early and prolonged anti-calcitonin gene-related peptide mAb treatment inhibited the development of the cephalic tactile pain hypersensitivity in both the severe and repetitive subconcussive head impact models. Conclusions Severe head injury gives rise to a prolonged state of cephalic and extracephalic tactile pain hypersensitivity. These pain behaviors also develop following repetitive, subconcussive head impacts. Extended cephalic tactile pain hypersensitivity following severe and repetitive mild closed head injury are ameliorated by early and prolonged anti-calcitonin gene-related peptide mAb treatment, suggesting a mechanism linked to calcitonin gene-related peptide signaling, potentially of trigeminal origin.

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Galcanezumab for the prevention of migraine

Pain Management ◽

10.2217/pmt-2020-0030 ◽

2020 ◽

Author(s):

Lindsay M Frerichs ◽

Deborah I Friedman

Keyword(s):

Monoclonal Antibody ◽

Clinical Efficacy ◽

Preventive Treatment ◽

Calcitonin Gene Related Peptide ◽

Efficacy And Safety ◽

Related Peptide ◽

Calcitonin Gene

Migraine is a common and disabling disorder affecting approximately 1.02 billion people worldwide. Calcitonin gene-related peptide (CGRP) has been identified as playing an important role in the pathophysiology of migraine and several migraine-specific therapies targeting the CGRP ligand or its receptor have been approved since 2018 for the acute and preventive treatment of migraine. This review focuses on the pharmacology, clinical efficacy and safety/tolerability of galcanezumab, an anti-CGRP monoclonal antibody approved for the prevention of migraine.

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The efficacy and safety of calcitonin gene-related peptide monoclonal antibody for episodic migraine: a meta-analysis

Neurological Sciences ◽

10.1007/s10072-018-3547-3 ◽

2018 ◽

Vol 39 (12) ◽

pp. 2097-2106 ◽

Cited By ~ 19

Author(s):

Yuhan Zhu ◽

Yanyan Liu ◽

Jing Zhao ◽

Qingqing Han ◽

Lei Liu ◽

...

Keyword(s):

Monoclonal Antibody ◽

Meta Analysis ◽

Episodic Migraine ◽

Calcitonin Gene Related Peptide ◽

Efficacy And Safety ◽

Related Peptide ◽

Calcitonin Gene

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Production and characterization of a monoclonal antibody against human calcitonin gene-related peptide (CGRP) and its immunohistochemical application to salivary glands

The Histochemical Journal ◽

10.1007/bf00157765 ◽

1994 ◽

Vol 26 (4) ◽

pp. 317-326 ◽

Cited By ~ 12

Author(s):

Ewa Szabat ◽

Antero Salo ◽

Ismo Virtanen ◽

Hannu Uusitalo ◽

Seppo Soinila

Keyword(s):

Monoclonal Antibody ◽

Salivary Glands ◽

Calcitonin Gene Related Peptide ◽

Human Calcitonin ◽

Related Peptide ◽

Calcitonin Gene

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Early clinical experience with a monoclonal antibody against the calcitonin gene-related peptide receptor in adolescents with migraine: A case series

Proceedings of Singapore Healthcare ◽

10.1177/2010105820935465 ◽

2020 ◽

Vol 29 (3) ◽

pp. 212-214

Author(s):

Yi Jing Zhao ◽

King-Hee Ho ◽

Pei Shieen Wong

Keyword(s):

Monoclonal Antibody ◽

Case Series ◽

Calcitonin Gene Related Peptide ◽

New Class ◽

Related Peptide ◽

Pediatric Migraine ◽

Calcitonin Gene ◽

Patient Reported ◽

Adolescent Patients ◽

Favorable Safety

Management of migraine in adolescents poses a great challenge, as many of the approved pharmacological migraine preventive agents have age restrictions. Following favorable safety and efficacy reports of the new class agent calcitonin gene-related peptide (CGRP) monoclonal antibody for use in migraine prevention, there is growing interest in its application in pediatric migraine. We present here a case series detailing our experience of using erenumab, a CGRP monoclonal antibody, in six adolescent patients. Two patients had a reduction of at least 50% in the mean number of monthly migraine days, one patient reported subjective improvement, while three patients did not respond to the first dose of erenumab and discontinued treatment. One patient reported constipation associated with erenumab use. We speculate that CGRP monoclonal antibody could potentially be a viable option in adolescent patients with migraine. Further evidences that support efficacy and safety of erenumab in this group is needed.

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Reversible cerebral vasoconstriction syndrome developing after an erenumab injection for migraine prevention

Cephalalgia ◽

10.1177/03331024211037277 ◽

2021 ◽

pp. 033310242110372

Author(s):

Todd D Rozen ◽

Alok A Bhatt

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Illicit Drugs ◽

Calcitonin Gene Related Peptide ◽

Reversible Cerebral Vasoconstriction Syndrome ◽

Related Peptide ◽

Cerebral Vasoconstriction ◽

Calcitonin Gene ◽

Preventive Medication ◽

New Type

Background Reversible cerebral vasoconstriction syndrome is normally triggered by vasoactive compounds or illicit drugs. A new type of migraine preventive medication blocks calcitonin gene-related peptide utilizing monoclonal antibodies. Calcitonin gene-related peptide is a potent vasodilator for the cerebrovascular system. Could blocking calcitonin gene-related peptide be a trigger for cerebral artery vasospasm in patients susceptible to developing reversible cerebral vasoconstriction syndrome (migraine patients) or in individuals using vasoactive compounds? We present a case of reversible cerebral vasoconstriction syndrome occurring after calcitonin gene-related peptide monoclonal antibody treatment. Case report A 43-year -old woman with a history of episodic migraine developed an acute headache with orgasm two days after taking her second injection of erenumab. Ten days after erenumab injection she developed a thunderclap headache while completing a high intensity workout. These new headaches were only left sided. Computed tomography angiography demonstrated mild to moderate areas of narrowing involving the left middle and anterior cerebral arteries, concerning for reversible cerebral vasoconstriction syndrome. She denied exposure to any known reversible cerebral vasoconstriction syndrome precipitant medication or illicit drugs. She did endorse recent exposure to high altitude prior to erenumab therapy. She was started on verapamil 40 mg three times per day and her headache ceased within 24 h of initiating treatment. A repeat CT angiogram completed 4 weeks after the initial study noted resolution of the areas of vessel stenosis. Conclusion A case of reversible cerebral vasoconstriction syndrome developing after treatment with a calcitonin gene-related peptide monoclonal antibody is presented. The timing of the new type of headache occurring 2 days post erenumab injection suggests a possible cause and effect relationship. Reversible cerebral vasoconstriction syndrome as a possible treatment-related complication to the usage of calcitonin gene-related peptide monoclonal antibodies needs to be studied further.

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Fremanezumab autoinjector pen for the prevention of migraine

Therapeutic Delivery ◽

10.4155/tde-2021-0028 ◽

2021 ◽

Author(s):

Mark W Weatherall

Keyword(s):

Monoclonal Antibody ◽

Clinical Trials ◽

Calcitonin Gene Related Peptide ◽

Phase Iii ◽

Tolerability Profile ◽

Related Peptide ◽

Phase Iii Clinical Trials ◽

Humanized Monoclonal Antibody ◽

Calcitonin Gene ◽

Favorable Tolerability Profile

Ajovy (fremanezumab, Teva Pharmaceuticals, Israel) is a fully humanized monoclonal antibody that selectively binds both isoforms of the calcitonin gene-related peptide. Calcitonin gene-related peptide is a 37-amino acid neuropeptide involved in central and peripheral pathophysiological events in migraine. It is indicated for prophylaxis of migraine in adults who have at least four migraine days per month, and can be administered as a subcutaneous injection using an autoinjector device, with two dosing options: 225 mg once a month or 675 mg quarterly. In this article, I present data from Phase III clinical trials of fremanezumab in episodic and chronic migraine, in which fremanezumab demonstrated efficacy and had a favorable tolerability profile, with no serious treatment-related adverse events.

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