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2013 and 2009 MRF Research Grantee
The Effects of Calcium Channel Mutations on Trigeminal Ganglion Neurons Innervating the Dura (2009)
Studying the effects of calcium channel mutations on nerves in the dura which contribute to migraine. (2009)
FINAL REPORT: Immunotherapy for Migraine Headache (2013)
Published in Pain, Volume 157, Issue 8, August 2016
Overproduction of proinflammatory cytokines and chemokines has been implicated in migraine pathogenesis in human studies. In the present study, we systematically investigated the expression profile of multiple cytokines and chemokines in a mouse model of headache. After inducing a ‘headache’ episode in mice, we found that the level of tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), interleukin 1β> (IL-1β) and interleukin 6 (IL-6) was significantly increased in the meninges, a likely source for the generation of migraine-related pain. The expression of TNF-α> and MCP-1 was also increased in the trigeminal ganglia (TG), where the cell bodies of the primary sensory neurons in the migraine circuit are localized. However, induction of one ‘headache’ episode did not significantly change the cytokine/chemokine profiles in mouse blood or cerebrospinal fluid (CSF).
Next, we generated neutralizing antibodies against these cytokines/chemokines and tested their effects in the headache model. We found that the TNF-α, MCP-1 and IL-6 neutralizing antibodies effectively blocked headache-like behavior in mice. Conversely, the IL-1β> antibodies were not effective. Lastly, we vaccinated mice to generate auto-antibodies against TNF-α, MCP-1 and IL-6, respectively. We found that the headache-like behavior was significantly reduced in mice with high titer auto-antibodies. Conversely, mice with lower titer auto-antibodies showed headache-like behavior similar to the control group.
Hypothesis v. Findings
Our original hypothesis was validated. We have shown that the expression level of multiple cytokines/chemokines is altered in the meninges and TG in a mouse model of headache. TNF-α, MCP-1 and IL-6 likely contribute to the onset of a headache episode, and therefore are potential targets for new anti-migraine drugs. On the other hand, IL-1β may be used as a biomarker for migraine but may not contribute to the migraine pathogenesis
The most important unanswered question is how proinflammatory cytokines/chemokines contribute to the pathophysiology of chronic migraine. Outstanding questions include: do cytokines/chemokines contribute to the transition from episodic to chronic migraine in the mouse model? Does the cytokine/chemokine profile change significantly in the mouse model of chronic migraine? And if so, can neutralizing antibodies prevent the transition from episodic to chronic migraine or even reverse the course of chronification? Understanding these questions will not only advance our knowledge on the pathogenesis of chronic migraine, but also help us identify potential targets for preventive treatment.
What this Research Means to You
The expression profile of the cytokines/chemokines may be used as biomarkers in stratifying migraine patients for personalized medicine. Reducing the level of TNF-α, MCP-1 or IL-6 may prevent the onset of headache in migraine patients. Passive immunotherapy (injection of neutralizing antibodies) may be more feasible than active immunotherapy (vaccination to generate auto-antibodies) as a treatment strategy.
FINAL REPORT: The Effects of Calcium Channel Mutations on Trigeminal Ganglion Neurons Innervating the Dura (2009)
Published in Molecular Pain, Volume 8, Issue 66, September 2012
Multiple mutations of human P/Q-type calcium channels are associated with familial hemiplegic migraine type 1, a rare hereditary form of migraine. Understanding how these channels contribute to the onset of headache will shed light on the mechanisms of migraine in general. In this project, we used leaner, a strain of mouse that has the mutant P/Q-type channels, as a model to investigate the effects of these channels on primary sensory neurons mediating migraine headache and facial pain.
The activation and sensitization of trigeminal ganglion (TG) neurons innervating the meninges and cerebral vessels in the brain is the first step in the onset of headache. We conducted electrophysiological recordings to compare the electrical properties of certain neurons from wild-type and leaner mice. We found that it is easier to excite a leaner neuron than a wild-type neuron. We conclude that mutant P/Q-type calcium channels may cause hyper-excitation of primary sensory neurons innervating the meninges and, in turn, lead to a higher susceptibility of migraine headache. As control experiments, we looked at TG neurons innervating the facial skin and studied their electric properties. Interestingly, the leaner mutation did not cause hyper-excitation of this population of TG neurons. Taken together, our results indicate that mutant P/Q-type channels selectively increase the excitability of TG neurons mediating migraine headache while sparing neurons transmitting other facial pain.
Hypotheses v. Findings
We validated our hypothesis. Our results indicate that the mutation preferentially causes the hyper-excitation of neurons mediating migraine headache but not those mediating facial pain. This points to a possible mechanism through which abnormal calcium channel activity contributes to the generation of migraine headache but not other types of pain.
Additional experiments will be necessary to address many unanswered questions from this study. For example, why does the mutant P/Q-type calcium channel cause hyper-excitation of primary sensory neurons mediating migraine headache but not those transmitting facial or somatic pain? Is the activity of other ion channels altered in neurons expressing mutant P/Q-type channels? And if so, how does that contribute to the onset of headache?
What this Research Means to You
Understanding the role of mutant PQ-type channels will not only advance our knowledge of migraine pathophysiology, but also will help us identify potential new targets for migraine treatment.