¹¹C-PK11195 PET for the In Vivo Evaluation of Neuroinflammation in the Rat Brain After Cortical Spreading Depression

Abstract

Neurogenic inflammation triggered by extravasation of plasma protein has been hypothesized as a key factor in the generation of the pain sensation associated with migraine. The principal immune cell that responds to this inflammation is the parenchymal microglia of the central nervous system. Methods: Using a PET technique with 11 , a PET ligand for peripheral type-benzodiazepine receptor, we evaluated the microglial activation in the rat brain after generation of unilateral cortical spreading depression, a stimulation used to bring up an experimental animal model of migraine. Results: We found a significant increase in the brain uptake of 11 C-PK11195, which was completely displaceable by the excess amounts of unlabeled ligands, in the ipsilateral hemisphere of the spreading depressiongenerated rats. Moreover, the binding potential of 11 C-PK11195 in the spreading depression-generated rats was significantly higher than that in the sham-operated control rats. Conclusion: These results suggest that as an inflammatory reaction, microglial cells are activated in response to the nociceptive stimuli induced by cortical spreading depression in the rat brain. Therefore, the 11 C-PK11195 PET technique could have a potential for diagnostic and therapeutic monitoring of neurologic disorders related to neuroinflammation such as migraine.

Role of cortical spreading depression in the pathophysiology of migraine

“…Such neurogenic inflammation is thought to trigger a headache via stimulation of trigeminal afferents. Consistent with this hypothesis, cortical SD induced intracranial neurogenic inflammation around the meningeal blood vessels [13][14][15] , and subsequent activation of both peripheral [16] and central [17] trigeminal nociceptive pathways has been described. Here, we review the experimental evidence mainly from neurophysiological studies that has advanced the understanding of whether and how the neurovascular phenomenon of cortical SD causes intracranial neurogenic inflammation, and subsequently participates in triggering a migraine headache.…”

“…Using [ 11 C]PK11195-PET imaging in rats, we demonstrated that unilateral cortical SD induces neurogenic inflammation in the ipsilateral cerebral hemisphere [14] . The highest [ 11 C]PK11195 radioactivity was seen in the initial area of the cortical SD (KCl-microinjected Yilong Cui, et al Role of cortical spreading depression in the pathophysiology of migraine 817 site), and moderate radioactivity was observed in the ipsilateral surrounding areas, but not in the corresponding contralateral areas.…”

“…A juxtacellular recording study has further revealed that the [14] ). S1BF), trunk region of the primary somatosensory cortex, secondary somatosensory cortex, insula, primary visual cortex and primary auditory cortex [81] .…”

“…Its expression is upregulated in activated microglia [66][67][68] , and the upregulation is well correlated with the state of activation [69][70][71] . 11 C-labeled PK11195 is a specific PET ligand for PBR to image activated microglia in the brain, and has been extensively used for quantitative evaluation of brain infl ammation by PET in a number of neurological disorders, such as stroke [72] , multiple sclerosis [69] , Alzheimer disease [73] , Parkinson disease [74] and Huntington disease [75] .Using [ 11 C]PK11195-PET imaging in rats, we demonstrated that unilateral cortical SD induces neurogenic inflammation in the ipsilateral cerebral hemisphere [14] . The highest [ 11 C]PK11195 radioactivity was seen in the initial area of the cortical SD (KCl-microinjected Yilong Cui, et al Role of cortical spreading depression in the pathophysiology of migraine 817 site), and moderate radioactivity was observed in the ipsilateral surrounding areas, but not in the corresponding contralateral areas.…”

Macro- and microstructural alterations in migraine and cluster headache

“…One hypothesis states that the depolarization wave progressing through the cortex has a central role in migraine pathomechanism [24]. The excessive activation might well be enough to induce in cellular damage, [14] kindle neuroinflammation and consequently cause pain [84][85][86]. CSD in animals upregulates the matrix metalloproteinase (MMP)-9 [87] and the activation of MMP can elicit the leakage of blood-brain barrier and lead to inflammatory response and neuronal damage [88].…”