Department of Biological Sciences, School of Science, Centre for Neuroscience, Xi'an Jiaotong-Liverpool University, Suzhou, China.
Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
J Headache Pain. 2024 Oct 11;25(1):175. doi: 10.1186/s10194-024-01875-3.
Src family kinases (SFKs) contribute to migraine pathogenesis, yet its role in regulating photophobia behaviour, one of the most common forms of migraine, remains unknown. Here, we addressed whether SFKs antagonism alleviates photophobia behavior and explored the underlying mechanism involving hypothalamus and trigeminal ganglion activity, as measured by the alteration of neuropeptide levels and transcriptome respectively.
A rapid-onset and injury-free mouse model of photophobia was developed following intranasal injection of the TRPA1 activator, umbellulone. The role of SFKs antagonism on light aversion was assessed by the total time the mouse stays in the light and transition times between the dark and light compartments. To gain insight to the preventive mechanism of SFKs antagonism, hypothalamic neuropeptides levels were assessed using enzyme linked immunofluorescent assay and trigeminal ganglion activity were assessed using RNA-sequencing and qPCR analysis.
SFKs antagonism by a clinically relevant SFKs inhibitor saracatinib reduced the total time in light and transition times in male mice, but not in females, suggesting SFKs play a crucial role in photophobia progressing and exhibit a male-only effect. SFKs antagonism had no effect on hypothalamic calcitonin gene-related peptide and pituitary adenylate cyclase-activating polypeptide levels of all mice investigated, suggesting the gender-different effect of saracatinib on light aversion appears to be independent of these hypothalamic neuropeptide levels. In trigeminal ganglion of male mice, photophobia is associated with profound alteration of differentially expressed genes, part of which were reversed by SFKs antagonism. Subsequent qPCR analysis showed SFKs antagonism displayed gender-different modulation of expression in some candidate genes, particularly noteworthy those encoding ion channels (trpm3, Scn8a), ATPase signaling (crebbp, Atp5α1) and kinase receptors (Zmynd8, Akt1).
In conclusion, our data revealed that SFKs antagonism reduced photophobia processing in male mice and exhibited gender-different modulation of trigeminal ganglion activity, primarily manifesting as alterations in the transcriptome profile. These findings underscore the potential of SFKs antagonism for allieving photophobia in males, highlighting its value in the emerging field of precision medicine.
Src 家族激酶（SFKs）参与偏头痛的发病机制，但它在调节光恐惧症行为中的作用（偏头痛最常见的形式之一）仍不清楚。在这里，我们研究了 SFKs 拮抗剂是否能缓解光恐惧症行为，并通过分别测量神经肽水平和转录组的变化来探索涉及下丘脑和三叉神经节活动的潜在机制。
通过鼻内注射 TRPA1 激活剂 Umbellulone，建立了一种快速发作且无损伤的光恐惧症小鼠模型。通过测量小鼠在亮区的停留总时间和在暗区与亮区之间的转换时间，评估 SFKs 拮抗剂对光回避的作用。为了深入了解 SFKs 拮抗剂的预防机制，使用酶联免疫荧光测定法评估下丘脑神经肽水平，使用 RNA-seq 和 qPCR 分析评估三叉神经节活性。
临床上相关的 SFKs 抑制剂 Saracatinib 通过 SFKs 拮抗作用减少了雄性小鼠在亮区的停留总时间和转换时间，但对雌性小鼠没有影响，这表明 SFKs 在光恐惧症进展中起着至关重要的作用，并表现出雄性特有的作用。SFKs 拮抗剂对所有研究的小鼠下丘脑降钙素基因相关肽和垂体腺苷酸环化酶激活肽水平没有影响，这表明 Saracatinib 对光回避的性别差异作用似乎与这些下丘脑神经肽水平无关。在雄性小鼠的三叉神经节中，光恐惧症与差异表达基因的深刻改变有关，其中一部分被 SFKs 拮抗剂逆转。随后的 qPCR 分析显示，SFKs 拮抗剂对一些候选基因的表达表现出性别差异的调节，尤其是那些编码离子通道（trpm3、Scn8a）、ATP 酶信号（crebbp、Atp5α1）和激酶受体（Zmynd8、Akt1）的基因。
总之，我们的数据表明，SFKs 拮抗剂减少了雄性小鼠的光恐惧症，并表现出对三叉神经节活动的性别差异调节，主要表现为转录组谱的改变。这些发现强调了 SFKs 拮抗剂缓解雄性光恐惧症的潜力，突出了其在精准医学这一新兴领域的价值。
