Cerebrolysin attenuates hyperalgesia, photophobia, and neuroinflammation in a nitroglycerin-induced migraine model in rats

Mahmoudi, Javad; Mohaddes, Gisou; Sadigh-Eteghad, Saeed; Karimi, Pouran; Rajabi, Mojgan; Reyhani-Rad, Siamak; Farajdokht, Fereshteh

doi:10.1016/j.brainresbull.2018.05.008

Cited by 32 publications

(34 citation statements)

References 80 publications

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“…Repeat injection of NTG produced marked thermal paw hyperalgesia on days 7, 9, and 11 compared with vehicle injection, which is consistent with the change in mechanical hyperalgesia. Similar effects were reported by Mahmoudi J et al, who showed that chronic NTG administration was able to evoke thermal hypersensitivity in Wistar rats [27]. Few studies have observed this thermal response in mice.…”

Section: Animal Model Of Chronic Migrainesupporting

confidence: 86%

Microglia P2X4R-BDNF signalling contributes to central sensitization in a recurrent nitroglycerin-induced chronic migraine model

Long

Pan

et al. 2020

J Headache Pain

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Background: According to our previous study, microglia P2X4 receptors (P2X4Rs) play a pivotal role in the central sensitization of chronic migraine (CM). However, the molecular mechanism that underlies the crosstalk between microglia P2X4Rs and neurons of the trigeminal nucleus caudalis (TNC) is not fully understood. Therefore, the aim of this study is to examine the exact P2X4Rs signalling pathway in the development of central sensitization in a CM animal model. Methods: We used an animal model with recurrent intermittent administration of nitroglycerin (NTG), which closely mimics CM. NTG-induced basal mechanical and thermal hypersensitivity were evaluated using a von Frey filament test and an increasing-temperature hot plate apparatus (IITC). We detected P2X4Rs, brain-derived neurotrophic factor (BDNF) and phosphorylated p38 mitogen-activated protein kinase (p-p38-MAPK) expression profiles in the TNC. We investigated the effects of a P2X4R inhibitor (5-BDBD) and an agonist (IVM) on NTG-induced hyperalgesia and neurochemical changes as well as on the expression of p-p38-MAPK and BDNF. We also detected the effects of a tropomyosin-related kinase B (TrkB) inhibitor (ANA-12) on the CM animal model in vivo. Then, we evaluated the effect of 5-BDBD and SB203580 (a p38-MAPK inhibitors) on the release and synthesis of BDNF in BV2 microglia cells treated with 50 μM adenosine triphosphate (ATP). Results: Chronic intermittent administration of NTG resulted in chronic mechanical and thermal hyperalgesia, accompanied by the upregulation of P2X4Rs and BDNF expression. 5-BDBD or ANA-12 prevented hyperalgesia induced by NTG, which was associated with a significant inhibition of the NTG-induced increase in phosphorylated extracellular regulated protein kinases (p-ERK) and calcitonin gene related peptide (CGRP) release in the TNC. Repeated administration of IVM produced sustained hyperalgesia and significantly increased the levels of pERK and CGRP release in the TNC. Activating P2X4Rs with ATP triggered BDNF release and increased BDNF synthesis in BV2 microglia, and these results were then reduced by 5-BDBD or SB203580. Conclusions: Our results indicated that the P2X4R contributes to the central sensitization of CM by releasing BDNF and promoting TNC neuronal hyper-excitability. Blocking microglia P2X4R-BDNF signalling may have an effect on the prevention of migraine chronification.

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Section: Animal Model Of Chronic Migrainesupporting

confidence: 86%

Microglia P2X4R-BDNF signalling contributes to central sensitization in a recurrent nitroglycerin-induced chronic migraine model

Long

Pan

et al. 2020

J Headache Pain

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“…The release of these neuropeptides in the central nervous system facilitate nociceptive signalling and in the periphery contribute to vasodilatation of meningeal vessels and neurogenic inflammation [37]. Based on our results probable that the CFA-induced CGRP and PACAP1-38 increase play crucial role in triggering central sensitization, thereby regulation of these peptides may influence the rate of mechanical hyperalgesia [38].…”

Section: Discussionmentioning

confidence: 61%

The effect of orofacial complete Freund’s adjuvant treatment on the expression of migraine-related molecules

et al. 2019

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Background: Migraine is a neurovascular primary headache disorder, which causes significant socioeconomic problems worldwide. The pathomechanism of disease is enigmatic, but activation of the trigeminovascular system (TS) appears to be essential during the attack. Migraine research of recent years has focused on neuropeptides, such as calcitonin generelated peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide 1-38 (PACAP1-38) as potential pathogenic factors and possible therapeutic offensives. The goal of present study was to investigate the simultaneous expression of CGRP and precursor of PACAP1-38 (preproPACAP) in the central region of the TS in a time-dependent manner following TS activation in rats. Methods: The right whisker pad of rats was injected with 50 μl Complete Freund's Adjuvant (CFA) or saline. A mechanical allodynia test was performed with von Frey filaments before and after treatment. Transcardial perfusion of the animals was initiated 24, 48, 72 and 120 h after injection, followed by the dissection of the nucleus trigeminus caudalis (TNC). After preparation, the samples were stored at − 80°C until further use. The relative optical density of CGRP and preproPACAP was analyzed by Western blot. One-way ANOVA and Kruskal-Wallis followed by Tukey post hoc test were used to evaluate the data. Regression analysis was applied to explore the correlation between neuropeptides expression and hyperalgesia. Results: Orofacial CFA injection resulted in significant CGRP and preproPACAP release in the TNC 24, 48, 72 and 120 h after the treatment. The level of neuropeptides reached its maximum at 72 h after CFA injection, corresponding to the peak of facial allodynia. Negative, linear correlation was detected between the expression level of neuropeptides and value of mechanonociceptive threshold. Conclusion: This is the first study which suggests that the expression of CGRP and preproPACAP simultaneously increases in the central region of activated TS and it influences the formation of mechanical hyperalgesia. Our results contribute to a better understanding of migraine pathogenesis and thereby to the development of more effective therapeutic approaches.

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“…There have been only a few other studies of the effects of cerebrolysin on pain. More recently, Mahmoudi et al () has reported cerebrolysin markedly reduced mechanical and thermal hyperalgesia in a nitroglycerin‐induced rat model of chronic migraine. Nitroglycerin, a nitric oxide donor, causes the release of endogenous nitric oxide and CGRP from the trigeminal nuclei, which increases the sensitivity of the trigeminovascular system to induce migraine (Ashina, Simonsen, Bendtsen, Jensen, & Olesen, ).…”

Section: Discussionmentioning

confidence: 98%

“…Cerebrolysin is a multimodal neuropeptide preparation, which can modify the neurotrophic factor and sonic hedgehog signaling pathways to produce a neuroprotective effect within the central nervous system. Cerebrolysin can penetrate the blood brain barrier (Akai et al, ; Bornstein et al, ; Muresanu et al, ; Stan, et al, ), improve functional cognitive outcomes in patients with dementia and traumatic brain injury, and improve neuro‐rehabilitation in patients with stroke (Gharagozli et al, ; Mahmoudi et al, ; Onose et al, ). More recently, there is evidence to suggest that cerebrolysin may also produce an anti‐inflammatory and analgesic effect (Dong et al, ; Mahmoudi et al, ; Malashenkova et al, ; Morales‐Medina, et al, ; Sharma et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Cerebrolysin can penetrate the blood brain barrier (Akai et al, ; Bornstein et al, ; Muresanu et al, ; Stan, et al, ), improve functional cognitive outcomes in patients with dementia and traumatic brain injury, and improve neuro‐rehabilitation in patients with stroke (Gharagozli et al, ; Mahmoudi et al, ; Onose et al, ). More recently, there is evidence to suggest that cerebrolysin may also produce an anti‐inflammatory and analgesic effect (Dong et al, ; Mahmoudi et al, ; Malashenkova et al, ; Morales‐Medina, et al, ; Sharma et al, ). With the increasing evidence of the benefit of cerebrolysin in inflammation, we aim to build upon the findings of our previous study (Morales‐Medina et al, ) by investigating the response to acute administration of cerebrolysin in another model of peripheral inflammation and also assess sex differences.…”

Section: Introductionmentioning

confidence: 99%

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Cerebrolysin improves peripheral inflammatory pain: Sex differences in two models of acute and chronic mechanical hypersensitivity

Morales‐Medina

Flores

Vallelunga

et al. 2019

Drug Development Research

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Chronic inflammatory pain is a major health problem worldwide with high prevalence in women.Cerebrolysin is a multimodal neuropeptide preparation that crosses the blood brain barrier and displays neuroprotective properties in aging and disease. Previously, we showed that cerebrolysin reduced mechanical allodynia in a model of persistent inflammation and pain. We aim to build upon the findings of our previous study by investigating the response to acute administration of cerebrolysin in two models of peripheral inflammation and assessing sex differences. We utilized the complete Freund's adjuvant (CFA) that produces maximal oedema and mechanical allodynia within days and carrageenan that produces similar effects within hours. Cerebrolysin reversed the mechanical allodynia in both sexes in CFA-treated rats. On the other hand, in rats treated with carrageenan, cerebrolysin was only effective in reducing mechanical allodynia in female rats. In conclusion, the present study shows that cerebrolysin effects may be sex-specific depending on different mechanisms that are at play in these two models of peripheral inflammatory pain. Further investigations are required to determine the factors contributing to sex differences. K E Y W O R D Sallodynia, carrageenan, cerebrolysin, CFA, hypersensitivity, neuropeptide, pain, peripheral inflammation, peripheral pain, sex differences

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Cerebrolysin attenuates hyperalgesia, photophobia, and neuroinflammation in a nitroglycerin-induced migraine model in rats

Cited by 32 publications

References 80 publications

Microglia P2X4R-BDNF signalling contributes to central sensitization in a recurrent nitroglycerin-induced chronic migraine model

Microglia P2X4R-BDNF signalling contributes to central sensitization in a recurrent nitroglycerin-induced chronic migraine model

The effect of orofacial complete Freund’s adjuvant treatment on the expression of migraine-related molecules

Cerebrolysin improves peripheral inflammatory pain: Sex differences in two models of acute and chronic mechanical hypersensitivity

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