Upregulation of silent information regulator 1 alleviates mitochondrial dysfunction in the trigeminal nucleus caudalis in a rat model of chronic migraine

Abstract

Although the mechanism of chronic migraine is still unclear, more and more studies have shown that mitochondrial dysfunction plays a possible role in migraine pathophysiology. Silent information regulator 1 (SIRT1) plays a vital role in mitochondrial dysfunction in many diseases. However, there is no research on the role of SIRT1 in mitochondrial dysfunction of chronic migraine. The aim of this study was to explore the role of SIRT1 in mitochondrial dysfunction in chronic migraine. A rat model was established through repeated dural infusions of inflammatory soup for 7 days to simulate chronic migraine attacks. Cutaneous hyperalgesia caused by the repeated infusions of inflammatory soup was detected using the von Frey test. Then, we detected SIRT1 expression in the trigeminal nucleus caudalis. To explore the effect of SIRT1 on mitochondrial dysfunction in chronic migraine rats, we examined whether SRT1720, an activator of SIRT1, altered mitochondrial dysfunction in chronic migraine rats. Repeated infusions of inflammatory soup resulted in cutaneous hyperalgesia accompanied by downregulation of SIRT1. SRT1720 significantly alleviated the cutaneous hyperalgesia induced by repeated infusions of inflammatory soup. Furthermore, activation of SIRT1 markedly increased the expression of peroxisome proliferator-activated receptor gamma-coactivator 1-alpha, transcription factor A, nuclear respiratory factor 1 and nuclear respiratory factor 2 mitochondrial DNA and increased the ATP content and mitochondrial membrane potential. Our results indicate that SIRT1 may have an effect on mitochondrial dysfunction in chronic migraine rats. Activation of SIRT1 has a protective effect on mitochondrial function in chronic migraine rats.

Energy metabolism disturbance in migraine: From a mitochondrial point of view

“…It plays a central role in controlling mitochondrial function and mitochondrial biogenesis and is a known positive regulator of mitochondrial function and oxidative metabolism ( Fernandez-Marcos and Auwerx, 2011 ; Wang et al, 2015 ). It was found that repeated infusion of inflammatory soup into the dura mater could decrease the expression of PGC-1α in the trigeminal nucleus caudalis (TNC) in SD rats ( Figure 4 ) ( Liang et al, 2021 ).…”

Could Experimental Inflammation Provide Better Understanding of Migraines?

“…As mentioned previously, releases of neuropeptides such as CGRP, substance P and PACAP-38 are notable components of NI and these peptides are also linked to migraine pathophysiology, especially CGRP. Chronic application of IS on the dura causes upregulation of CGRP genes [ 62 , 63 , 66 , 67 , 73 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ] and Substance P [ 76 , 80 , 81 , 82 ] in the TGVS. PACAP-38 is increased in the plasma of migraineurs during attacks but reduced in chronic migraineurs [ 84 , 85 ].…”

“…Other notable pathological alterations caused by IS application to the dura include a decrease of 5-HT in the brain [ 65 ], an increase in the 5-HT 7 receptor expression [ 64 ], a decrease in α7nACh receptor expression in the hippocampus [ 75 ], an increase in nitric oxide (NO) [ 79 ], increases in the warm receptor TRPV1 [ 65 ] and cold receptor TRPM8 [ 87 ] expression, decreases in SIRT1 and PGC-1α [ 80 ], mitochondrial dysfunction [ 80 , 88 ], an altered functional connectivity between various brain regions [ 68 , 89 , 90 , 91 , 92 ], an increase in EphB2/EphrinB2 receptors [ 81 ], increased synaptic plasticity in TNC [ 76 , 79 , 81 ] but decreased plasticity in the hippocampus [ 93 ], an increase in glutamate in the TNC [ 94 ], an increase in mGluR5 [ 95 ], a decrease in GABA [ 94 ], decreases in GABABR1 and GABABR2 [ 94 ], increases in mTOR and autophagy [ 95 ], an increase in ASIC3 receptor expression [ 66 , 82 ], the increase of nNOS in the brain of rhesus monkeys [ 83 ], the impairment of descending inhibitory pathways [ 96 ], an increase in nerve growth factor (NGF) [ 66 ], increases of the P2Y 14 receptor [ 59 ] and the P2X 4 receptor expression [ 67 ], an increase in BBB permeability [ 74 , 97 ], the increase of VEGF [ 97 ], the sensitization of trigeminovascular neurons [ 96 , 98 , 99 , 100 , 101 ], an increase in white matter in different brain regions [ 102 ] and changes in the gut microbiota [ 65 ]. The application of other c...…”

“…Treatments that can reduce the pathological changes of the chemical stimulants may give indications of what could be potential migraine treatments and could be used as positive controls in future studies that will use this model. Treatments that managed to reduce periorbital and/or plantar allodynia or other pathologies induced by IS application to the dura include sumatriptan [ 65 , 97 , 108 ], ketoprofen (NSAID) [ 73 ], nimesulide (NSAID) [ 73 ], etoricoxib (NSAID) [ 73 ], baclofen (GABA B receptor agonist) [ 95 ], propranolol (β-blocker) [ 101 ], amitriptyline (tricyclic antidepressant) [ 93 ], minocycline (tetracycline-derived antibiotic) [ 70 ], rapamycin (mTOR inhibitor) [ 95 ], anti-IL18 [ 69 ], anti-NGF [ 66 ], flunarizine (calcium channel blocker) [ 62 ], H89 (PKA inhibitor) [ 94 ], chelerythrin (PKC blocker) [ 66 ], APETx2 (ASIC3 inhibitor) [ 82 ], MPEP (mGluR5 antagonist) [ 95 ], PNU-282987 (α7nACh receptor agonist) [ 75 ], TNP-ATP (P2X inhibitor) [ 67 ], ibudilast (PDE inhibitor) [ 70 ], electroacupuncture [ 64 , 100 , 109 ], EphB1-Fc (EphB receptor inhibitor; only 0.5 µg) [ 81 ], TAK-242 (TLR4 inhibitor) [ 71 ], naltrexone (TLR4 antagonist) [ 70 ], PP2 (NR2B-pTyr inhibitor) [ 76 ], genistein (protein tyrosine kinase inhibitor) [ 76 ], ANA-12 (TrkB antagonist) [ 67 ], SIRT1720 (SIRT1 activator) [ 80 ], xiongmatang extract [ 62 ], and wuzhuyu decoction [ 65 ]. Meanwhile, treatments using APETx2 [ 104 ], ANA-12 [ 104 ], anisomycin (protein synthesis inhibitor) [ 110 ], 4EGI-1 (translation initiation inhibitor) [ 110 ] or U0126 (MEK inhibitor) [ 107 ] alleviated IL-6 induced periorbital/plantar allodynia.…”

SS-31 alleviated nociceptive responses and restored mitochondrial function in a headache mouse model via Sirt3/Pgc-1α positive feedback loop

“…Of note, several nutrients targeting energy production and mitochondrial metabolism have shown efficacy in preventing migraine, such as riboflavin, coenzyme Q 10 , thiamine and niacin [ 7 – 9 ]. In migraine rodent models, mitochondrial dysfunction was also observed [ 10 ]. Thus, improving mitochondrial function has promise as an effective treatment for migraine.…”