Proteomics profiling reveals mitochondrial damage in the thalamus in a mouse model of chronic migraine.

BACKGROUND: Migraine, a complex brain disorder, is regarded as a possible clinical manifestation of brain energy dysfunction. The trigeminovascular system is considered the basis for the pathogenesis of migraine, hence we depicted the proteomics profiling of key regions in this system, then focusing on protein alterations related to mitochondrial function. The aim of this study is to illustrate the role of mitochondria in migraine. METHODS: A mouse model of chronic migraine (CM) was established by repeated nitroglycerin (NTG) stimulation and evaluated by von-Frey filaments, a hot plate and a light-dark box. Differentially expressed proteins (DEPs) in some subcortical brain regions of the trigeminovascular system were screened through liquid chromatography-tandem mass spectrometry (LC‒MS/MS) to analyse the specificity of key signaling pathways in different brain regions. And then mitochondrial function, structure and dynamics were determined by qPCR, ELISA, and transmission electron microscope (TEM). Finally, the effect of mitochondrial intervention-Urolithin A (UA) on CM was investigated. RESULTS: Repeated NTG injection triggered photophobia, periorbital and hind paw allodynia in mice. The proteomics profiling of CM model showed that 529, 109, 163, 152 and 419 DEPs were identified in the thalamus, hypothalamus, periaqueductal grey (PAG), trigeminal ganglion (TG) and trigeminocervical complex (TCC), respectively. The most significant changes in the brain region-specific pathways pointed to thalamic mitochondrial impairment. NTG induced mitochondrial structural disruption, dysfunction and homeostatic dysregulation, which could be partially attenuated by UA intervention. CONCLUSION: Our findings highlight the involvement of mitochondrial damage in the thalamus in central sensitization of CM, which provides evidence of possible metabolic mechanisms in migraine pathophysiology.

Abnormal Thalamo-Cortical Interactions in Overlapping Communities of Migraine: An Edge Functional Connectivity Study.

OBJECTIVE: Migraine has been demonstrated to exhibit abnormal functional connectivity of large-scale brain networks, which is closely associated with its pathophysiology and has not yet been explored by edge functional connectivity. We used an edge-centric approach combined with motif analysis to evaluate higher-order communication patterns of brain networks in migraine. METHODS: We investigated edge-centric metrics in 108 interictal migraine patients and 71 healthy controls. We parcellated the brain into networks using independent component analysis. We applied edge graph construction, k-means clustering, community overlap detection, graph-theory-based evaluations, and clinical correlation analysis. We conducted motif analysis to explore the interactions among regions, and a classification model to test the specificity of edge-centric results. RESULTS: The normalized entropy of lateral thalamus was significantly increased in migraine, which was positively correlated with the baseline headache duration, and negatively correlated with headache duration reduction following preventive medications at 3-month follow-up. Network-wise entropy of the sensorimotor network was significantly elevated in migraine. The community similarity between lateral thalamus and postcentral gyrus was enhanced in migraine. Migraine patients showed overrepresented L-shape and diverse motifs, and underrepresented forked motifs with lateral thalamus serving as the reference node. Furthermore, migraine patients presented with overrepresented L-shape triads, where the postcentral gyrus shared different edges with the lateral thalamus. The classification model showed that entropy of the lateral thalamus had the highest discriminative power, with an area under the curve of 0.86. INTERPRETATION: Our findings indicated an abnormal higher-order thalamo-cortical communication pattern in migraine patients. The thalamo-cortical-somatosensory disturbance of concerted working may potentially lead to aberrant information flow and deficit pain processing of migraine. ANN NEUROL 2023;94:1168-1181.

Mechanisms of Chinese herb emodin and somatostatin analogs on pancreatic regeneration in acute pancreatitis in rats.

INTRODUCTION: Studies have revealed that emodin is a potent agent in the management of clinical and experimental acute pancreatitis, but the molecular mechanisms by which emodin produces its biologic effects, especially on pancreatic regeneration after acute pancreatitis, remain unknown. Numerous experimental and clinical studies have shown that somatostatin analogs have favorable effects on acute pancreatitis, but their role in the management of acute pancreatitis remains controversial. AIM: To investigate mechanisms of the Chinese herb emodin and somatostatin analogs (SSa; Sandostatin) in acute pancreatitis of rats by analyzing the changes in pancreatic tissue cytokine transforming growth factor beta1 (TGFbeta1) and epidermal growth factor (EGF) gene expression, DNA synthesis, total protein content, and the relations between them. METHODOLOGY: Acute pancreatitis was induced by intraperitoneal infusion of cerulein in rats. Emodin was administered intravenously and Sandostatin was administered subcutaneously at the time of induction of pancreatitis and 24, 48, and 72 hours afterward. Rats were killed at 6, 24, 48, 72, and 96 hours after the operation. The mRNA expression of TGFbeta1 and EGF were evaluated by reverse transcription polymerase chain reaction, and pancreatic tissue DNA synthesis was measured by the 3H-thymidine incorporation method in vitro. Total protein content was detected by Lowry's method. RESULTS: The serum amylase level was decreased significantly in the emodin-treated and Sandostatin-treated groups in comparison with the nontreated group. Pancreatic tissue DNA synthesis was significantly decreased at 72 hours after the induction of pancreatitis, and a marked increase was observed at 96 hours after treatment with emodin and Sandostatin. Within 48 hours of the induction of pancreatitis, the total protein content in pancreatic tissue declined, but there was a remarkable increase in the emodin-treated group at 96 hours and Sandostatin-treated group at 48 hours. Expression of TGFbeta1 mRNA and EGF mRNA were undetectable in normal pancreas and the nontreated group at 6 hours but was observed from 24 hours to 96 hours after the induction of pancreatitis and reached its maximum at 72 hours. TGFbeta1 mRNA could be detected 6 hours after treatment with emodin and Sandostatin, and its expression was significantly higher in the emodin-treated and Sandostatin-treated groups than in the nontreated group at 24 and 48 hours. The expression of EGF mRNA was significantly higher in the emodin-treated and Sandostatin-treated group than in the nontreated group at 48 hours. CONCLUSION: It was concluded that mechanisms of the Chinese herb emodin and somatostatin analogs in the management of acute pancreatitis in rats might be ascribed to the upregulation of TGFbeta1 and EGF gene expression, which subsequently increases DNA synthesis and protein content and thus accelerates pancreatic repair and regeneration.