OBJECTIVE: Genetic and environmental factors interact in the development of major depressive disorder (MDD). While neurobiological correlates have only partially been elucidated, altered levels of calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) in animal models and in the cerebrospinal fluid of depressed patients were reported, suggesting that CGRP may be involved in the pathophysiology and/or be a trait marker of MDD. However, changes in CGRP brain levels resulting from interactions between genetic and environmental risk factors and the response to antidepressant treatment have not been explored. METHODS: We therefore superimposed maternal separation (MS) onto a genetic rat model (Flinders-sensitive and -resistant lines, FSL/FRL) of depression, treated these rats with antidepressants (escitalopram and nortriptyline) and measured CGRP-LI in selected brain regions. RESULTS: CGRP was elevated in the frontal cortex, hippocampus and amygdala (but not in the hypothalamus) of FSL rats. However, MS did not significantly alter levels of this peptide. Likewise, there were no significant interactions between the genetic and environmental factors. Most importantly, neither escitalopram nor nortriptyline significantly altered brain CGRP levels. CONCLUSION: Our data demonstrate that increased brain levels of CGRP are present in a well-established rat model of depression. Given that antidepressants have virtually no effect on the brain level of this peptide, our study indicates that further research is needed to evaluate the functional role of CGRP in the FSL model for depression.

• Klíčová slova
• Flinders-sensitive line, calcitonin gene-related peptide, escitalopram, maternal deprivation, nortriptyline,
• MeSH
• amygdala účinky léků   metabolismus   MeSH
• antidepresiva farmakologie   MeSH
• čelní lalok účinky léků   metabolismus   MeSH
• citalopram farmakologie   MeSH
• deprese * farmakoterapie   etiologie   metabolismus   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• interakce genů a prostředí * MeSH
• krysa rodu Rattus MeSH
• maternální deprivace * MeSH
• modely nemocí na zvířatech MeSH
• mozek * účinky léků   metabolismus   MeSH
• nortriptylin farmakologie   MeSH
• peptid spojený s genem pro kalcitonin * účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antidepresiva MeSH
• citalopram MeSH
• nortriptylin MeSH
• peptid spojený s genem pro kalcitonin * MeSH

Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals. In this study, we used mouse and rat skin preparations and enzyme-linked immunosorbent assays (ELISA) to study the molecular mechanism by which P-CTX-1 induces CGRP release. We show that P-CTX-1 induces CGRP release more effectively in mouse as compared to rat skin, exhibiting EC50 concentrations in the low nanomolar range. P-CTX-1-induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP) ion channels. In contrast, lidocaine and tetrodotoxin (TTX) reduce CGRP release by 53-75%, with the remaining fraction involving L-type and T-type voltage-gated calcium channels (VGCC). Using transgenic mice, we revealed that the TTX-resistant voltage-gated sodium channel (VGSC) NaV1.9, but not NaV1.8 or NaV1.7 alone and the combined activation of the TTX-sensitive VGSC subtypes NaV1.7 and NaV1.1 carry the largest part of the P-CTX-1-caused CGRP release of 42% and 34%, respectively. Given the contribution of CGRP to nociceptive and itch sensing pathways, our findings contribute to a better understanding of sensory symptoms of acute and chronic ciguatera that may help in the identification of potential therapeutics.

• Klíčová slova
• P-CTX-1, TRPA1, TRPC5, TRPM8, TTX, calcitonin-gene related peptide, ciguatera, neurogenic inflammation, neuropathic pain, tetrodotoxin, voltage-gated calcium channels,
• MeSH
• ciguatera metabolismus   MeSH
• ciguatoxiny chemie   farmakologie   MeSH
• ELISA MeSH
• hyperalgezie chemicky indukované   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• lidokain farmakologie   MeSH
• membránové potenciály účinky léků   MeSH
• mořské toxiny farmakologie   MeSH
• myši transgenní MeSH
• myši MeSH
• napětím řízený sodíkový kanál, typ 1 účinky léků   MeSH
• napětově řízený sodíkový kanál typ 11 účinky léků   MeSH
• napěťově řízený sodíkový kanál, typ 9 účinky léků   MeSH
• peptid spojený s genem pro kalcitonin účinky léků   MeSH
• receptory peptidu se vztahem ke genu kalcitoninu účinky léků   MeSH
• tetrodotoxin farmakologie   MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CALCA protein, human MeSH Prohlížeč
• ciguatoxiny MeSH
• lidokain MeSH
• mořské toxiny MeSH
• napětím řízený sodíkový kanál, typ 1 MeSH
• napětově řízený sodíkový kanál typ 11 MeSH
• napěťově řízený sodíkový kanál, typ 9 MeSH
• peptid spojený s genem pro kalcitonin MeSH
• receptory peptidu se vztahem ke genu kalcitoninu MeSH
• tetrodotoxin MeSH
• vápník MeSH

INTRODUCTION: Assessing the impact of migraine preventive treatments on acute medication consumption is important in clinical evaluation. The number of acute medication intakes per each monthly migraine day (MMD) could provide insights on migraine burden and represent a new proxy of treatment effectiveness in clinical trials and real-life studies. We evaluated the effect of monoclonal antibodies acting on calcitonin gene-related peptide (CGRP) pathway on the consumption of migraine acute medication in real-life. METHODS: In two headache centers in Prague (CZ), we included and followed up to 6 months consecutive patients treated with MoAbs acting on CGRP (erenumab or fremanezumab). For each month of treatment, we reported monthly drug intake (MDI) in doses of any medication, migraine-specific (MS), and non-migraine-specific (non-MS) medications, and computed a ratio between MMDs and MDI, i.e., Migraine Medication Index (MMI) for MS and non-MS medications. RESULTS: We included 90 patients (91.1% women) with a median age of 47 [interquartile range (IQR) 42-51] years; 81 (90.0%) treated with erenumab and 9 (10.0%) with fremanezumab. Median MMDs decreased from 11 (IQR 8-14) at baseline to 4 (IQR 2-5) at Month 3 (p < 0.001 vs. baseline) and 3 (IQR 2-6) at Month 6 (p < 0.001 vs. baseline). Median MDI decreased from 15 drug intakes (IQR 11-20) at baseline to four drug intakes (IQR 2-7) at Month 3 (p < 0.001) and four drug intakes (IQR 2-7) at Month 6 (p < 0.001).The corresponding MDIs for MS medications were 10 (IQR 6-14) at baseline, 3 (IQR 1-5, p < 0.001) at Month 3, and 2 (IQR 0-4, p < 0.001) at Month 6. Monthly drug intakes for non-MS medications were 4 (IQR 0-9) at baseline, 1 (IQR 0-3, p < 0.001) at Month 3 and at Month 6.Median MMI decreased from 1.32 (IQR 1.11-1.68) at baseline to 1.00 (IQR 1.00-1.50, p < 0.001) at Month 3 and 1.00 (IQR 1.00-1.34, p < 0.001) at Month 6. CONCLUSIONS: We confirmed that MoAbs acting on CGRP pathway decrease acute migraine medication consumption. We proposed a new index that can be easily applied in clinical practice to quantify migraine burden and its response to acute medication. Our index could help optimizing migraine acute treatment in clinical practice.

• Klíčová slova
• calcitonin gene-related peptide (CGRP), medication, migraine acute treatment, monoclonal antibodies, real-life,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Monoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or its receptor have changed migraine preventive treatment. Those treatments have led to reconsidering the outcomes of migraine prevention. Available data mostly considered benefits in terms of relative efficacy (percent or absolute decrease in monthly migraine days [MMDs] or headache days compared with baseline). However, not enough attention has been paid to residual MMDs and/or migraine-related disability in treated patients. In the present study, we aimed at comparing the relative and absolute efficacy of erenumab. METHODS: ESTEEMen was a collaborative project among 16 European headache centers which already performed real-life data collections on patients treated with erenumab for at least 12 weeks. For the present study, we performed a subgroup analysis on patients with complete data on MMDs at baseline and at weeks 9-12 of treatment. Starting from efficacy thresholds proposed by previous literature, we classified patients into 0-29%, 30-49%, 50-74%, and ≥75% responders according to MMD decrease from baseline to weeks 9-12 of treatment. For each response category, we reported the median MMDs and Headache Impact test-6 (HIT-6) scores at baseline and at weeks 9-12. We categorized the number of residual MMDs at weeks 9-12 as follows: 0-3, 4-7, 8-14, ≥15. We classified HIT-6 score into four categories: ≤49, 50-55, 56-59, and ≥60. To keep in line with the original scope of the ESTEEMen study, calculations were performed in men and women. RESULTS: Out of 1215 patients, at weeks 9-12, 381 (31.4%) had a 0-29% response, 186 (15.3%) a 30-49% response, 396 (32.6%) a 50-74% response, and 252 (20.7%) a ≥75% response; 246 patients (20.2%) had 0-3 residual MMDs, 443 (36.5%) had 4-7 MMDs, 299 (24.6%) had 8-14 MMDs, and 227 (18.7%) had ≥15 MMDs. Among patients with 50-74% response, 246 (62.1%) had 4-7 and 94 (23.7%) 8-14 residual MMDs, while among patients with ≥75% response 187 (74.2%) had 0-3 and 65 (25.8%) had 4-7 residual MMDs. CONCLUSIONS: The present study shows that even patients with good relative response to erenumab may have a clinically non-negligible residual migraine burden. Relative measures of efficacy cannot be enough to thoroughly consider the efficacy of migraine prevention.

• Klíčová slova
• Erenumab, Migraine frequency, Real-world, Treatment efficacy,
• MeSH
• antagonisté CGRP receptorů farmakologie   terapeutické užití   MeSH
• humanizované monoklonální protilátky * terapeutické užití   MeSH
• lidé MeSH
• migréna * farmakoterapie   prevence a kontrola   MeSH
• peptid spojený s genem pro kalcitonin MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• antagonisté CGRP receptorů MeSH
• erenumab MeSH Prohlížeč
• humanizované monoklonální protilátky * MeSH
• peptid spojený s genem pro kalcitonin MeSH

Alcohol binge drinking is common among adolescents and may challenge the signalling systems that process affective stimuli, including calcitonin gene-related peptide (CGRP) signalling. Here, we employed a rat model of adolescent binge drinking to evaluate reward-, social- and aversion-related behaviour, glucocorticoid output and CGRP levels in affect-related brain regions. As a potential rescue, the effect of the phytocannabinoid cannabidiol was explored. Adolescent male rats underwent the intermittent 20% alcohol two-bottle choice paradigm; at the binge day (BD) and the 24 h withdrawal day (WD), we assessed CGRP expression in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, hypothalamus and brainstem; in addition, we evaluated sucrose preference, social motivation and drive, nociceptive response, and serum corticosterone levels. Cannabidiol (40 mg/kg, i.p.) was administered before each drinking session, and its effect was measured on the above-mentioned readouts. At BD and WD, rats displayed decreased CGRP expression in mPFC, NAc and amygdala; increased CGRP levels in the brainstem; increased response to rewarding- and nociceptive stimuli and decreased social drive; reduced serum corticosterone levels. Cannabidiol reduced alcohol consumption and preference; normalised the abnormal corticolimbic CGRP expression, and the reward and aversion-related hyper-responsivity, as well as glucocorticoid levels in alcohol binge-like drinking rats. Overall, CGRP can represent both a mediator and a target of alcohol binge-like drinking and provides a further piece in the intricate puzzle of alcohol-induced behavioural and neuroendocrine sequelae. CBD shows promising effects in limiting adolescent alcohol binge drinking and rebalancing the bio-behavioural abnormalities.

• Klíčová slova
• CGRP, adolescent alcohol binge drinking, cannabidiol, corticosterone, reward/aversion,
• MeSH
• ethanol MeSH
• glukokortikoidy MeSH
• hypothalamus MeSH
• kanabidiol * farmakologie   MeSH
• kortikosteron MeSH
• krysa rodu Rattus MeSH
• nárazové pití alkoholu * farmakoterapie   metabolismus   psychologie   MeSH
• peptid spojený s genem pro kalcitonin metabolismus   MeSH
• pití alkoholu škodlivé účinky   metabolismus   psychologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ethanol MeSH
• glukokortikoidy MeSH
• kanabidiol * MeSH
• kortikosteron MeSH
• peptid spojený s genem pro kalcitonin MeSH

Substance P (SP) and calcitonin gene-related peptide (CGRP) have been found in the perichondrium and within the cartilage canals. It is still unknown whether they exert a direct effect on chondrocytes during joint development. We processed 28 knees of newborn Wistar rats in 7 different fashions to perform histology and immunohistochemistry studies. Positive immunoreactivity against CGRP and SP was found in the inner aspect of the perichondrium in a close contact with chondrocytes. The presence of CGRP and SP indicates the presence of nerves fibers, and precedes the development of cartilage canals. Nerve fibers may play a role in the development of synovial joints before and during the presence of cartilage canals. The presence of CGRP and SP in the cartilage at birth may be involved in the early postnatal maturation of synovial joints. It remains to be determined whether autonomic innervation is later involved in age-related degenerative joint disease.

• MeSH
• kloubní chrupavka cytologie   metabolismus   MeSH
• kolenní kloub cytologie   metabolismus   MeSH
• krysa rodu Rattus MeSH
• novorozená zvířata MeSH
• peptid spojený s genem pro kalcitonin metabolismus   MeSH
• potkani Wistar MeSH
• substance P metabolismus   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• peptid spojený s genem pro kalcitonin MeSH
• substance P MeSH

Calcitonin gene-related peptide (CGRP) is a vasorelaxant and positive inotropic and chronotropic peptide that binds to the calcitonin receptor-like receptor. In the heart, upon stimulation CGRP is released from sensory nerve terminals and improves cardiac perfusion and function. In the present study, we investigated alterations in the components of the CGRP signaling system during development of diabetic cardiomyopathy. Rats received a single injection of streptozotocin. Four, 8, and 16 weeks thereafter cardiac CGRP content (radioimmunoassay), calcitonin receptor-like receptor expression (by real-time RT-PCR), and CGRP and calcitonin receptor-like receptor tissue distribution (immunohistochemistry) were assessed. CGRP content of atria and ventricles progressively increased during the 4 months following streptozotocin-treatment, while the distribution of CGRP-immunoreactive fibers was not visibly altered. Conversely, cardiac expression of calcitonin receptor-like receptor initially (4 weeks after treatment) increased but then gradually declined to 47% of control levels in both atria after 16 weeks. These quantitative changes were not associated with altered cellular distribution patterns (primarily in venous and capillary endothelium). Since sensory neurons have been reported to decrease expression of the CGRP precursor in the course of diabetes, the intra-axonal accumulation of CGRP observed here reflects impaired release, which, coupled with the down-regulation of its cognate receptor, calcitonin receptor-like receptor, may contribute to the well-documented impairment of cardioprotective functions in diabetes.

• MeSH
• analýza rozptylu MeSH
• axony metabolismus   MeSH
• časové faktory MeSH
• experimentální diabetes mellitus komplikace   metabolismus   MeSH
• funkční lateralita MeSH
• imunohistochemie metody   MeSH
• kardiomyopatie etiologie   metabolismus   MeSH
• krysa rodu Rattus MeSH
• messenger RNA metabolismus   MeSH
• peptid spojený s genem pro kalcitonin metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí metody   MeSH
• potkani Wistar MeSH
• radioimunoanalýza metody   MeSH
• receptory peptidu se vztahem ke genu kalcitoninu metabolismus   MeSH
• regulace genové exprese účinky léků   fyziologie   MeSH
• srdeční komory metabolismus   MeSH
• srdeční síně metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• messenger RNA MeSH
• peptid spojený s genem pro kalcitonin MeSH
• receptory peptidu se vztahem ke genu kalcitoninu MeSH

Vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI) and calcitonin gene-related peptide (CGRP)-LI concentrations were determined in the developing rat heart atria using radioimmunoassay. Peptide levels were analysed on postnatal days 1, 10, 25, 45, 60, and 85 (P1-P85) separately in the right (RA) and left atria (LA). No sex differences were revealed at any age examined. VIP-LI has been already detected in both atria at P1 in concentrations comparable to values at P10. In the RA, VIP-LI levels increased significantly between days P10 and P25, remained high at P45 and then declined. In the LA, VIP-LI concentrations did not differ from those in the RA on days P1, P10, P25, and P45. However, regional differences were found at P60 and P85, when the peptide levels were significantly higher in the LA than in the RA. The postnatal changes in CGRP-LI concentrations were comparable in both atria with similar values at P1 and P85. After birth, CGRP levels decreased gradually till P45, then they increased till P60 and declined again at P85. The results demonstrate that there is an asymmetry in the postnatal development of the atrial VIP-LI and CGRP-LI concentrations. VIP-LI levels reached their maximum at P25, whereas CGRP-LI levels at P60. Relatively high peptide concentrations in neonatal atria and their variations during development might be related to diverse trophic functions of VIP and CGRP.

• MeSH
• autonomní nervové dráhy cytologie   růst a vývoj   metabolismus   MeSH
• krysa rodu Rattus MeSH
• peptid spojený s genem pro kalcitonin metabolismus   MeSH
• potkani Wistar MeSH
• srdeční síně cytologie   růst a vývoj   inervace   metabolismus   MeSH
• tělesná hmotnost fyziologie   MeSH
• vazoaktivní intestinální peptid metabolismus   MeSH
• velikost orgánu fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• peptid spojený s genem pro kalcitonin MeSH
• vazoaktivní intestinální peptid MeSH

The membrane actions of calcitonin gene-related peptide (CGRP) and the effect of CGRP on the Ca-dependent action potential of rat dorsal root ganglion (DRG) neurons have been studied by means of an intracellular recording technique in isolated DRG of 2-3-week-old rats in vitro. Bath application of CGRP (10(-8)-10(-6) M for 1-5 min) elicited a slow reversible hyperpolarization and this hyperpolarizing effect was still observed in the medium containing TTX and TEA. However, about half of the large cells, classified by duration of action potential, were depolarized by CGRP. These membrane effects of CGRP were associated with an increase in membrane input resistance (about 20%). In addition, CGRP increased the duration of Ca-dependent action potentials. Our results are consistent with the role of CGRP as an excitatory neurotransmitter or neuromodulator in DRG-spinal cord.

• MeSH
• evokované potenciály účinky léků   MeSH
• inbrední kmeny potkanů MeSH
• kalcitonin farmakologie   MeSH
• krysa rodu Rattus MeSH
• neurony aferentní účinky léků   fyziologie   MeSH
• neuropeptidy farmakologie   MeSH
• peptid spojený s genem pro kalcitonin MeSH
• referenční hodnoty MeSH
• spinální ganglia účinky léků   fyziologie   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kalcitonin MeSH
• neuropeptidy MeSH
• peptid spojený s genem pro kalcitonin MeSH

The effects of calcitonin gene-related peptide (CGRP) on the transient outward current (Ito) and the L-type calcium current (ICa,L) were investigated in isolated rat ventricular cardiomyocytes using the whole-cell, patch-clamp technique. CGRP influenced neither the amplitude nor the time course of ICa,L. On the other hand, at all membrane potentials at which a significant Ito was elicited, CGRP decreased its amplitude. The effect on Ito was completely reversible and independent of membrane potential. The steady-state activation and inactivation curves of Ito were not influenced by CGRP. The time course of Ito inactivation was satisfactorily fitted by two exponentials. Both the fast and the slow time constants of inactivation were voltage independent and were not influenced by CGRP. The effect of CGRP on Ito was concentration dependent with half-maximum inhibition at 99 nM. Chelerythrine, a selective inhibitor of protein kinase C, prevented the effect of CGRP on Ito. The data indicate that CGRP suppresses Ito in a concentration-dependent, but membrane potential-independent manner and that the effect is probably mediated via a protein kinase C-dependent pathway.

• MeSH
• akční potenciály účinky léků   MeSH
• alkaloidy MeSH
• benzofenantridiny MeSH
• elektrická vodivost * MeSH
• fenantridiny farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• kinetika MeSH
• krysa rodu Rattus MeSH
• metoda terčíkového zámku MeSH
• peptid spojený s genem pro kalcitonin farmakologie   MeSH
• proteinkinasa C antagonisté a inhibitory   metabolismus   MeSH
• srdce - funkce komor MeSH
• srdce fyziologie   MeSH
• srdeční komory cytologie   MeSH
• vápníkové kanály - typ L účinky léků   fyziologie   MeSH
• vápníkové kanály - typ T účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alkaloidy MeSH
• benzofenantridiny MeSH
• chelerythrine MeSH Prohlížeč
• fenantridiny MeSH
• inhibitory enzymů MeSH
• peptid spojený s genem pro kalcitonin MeSH
• proteinkinasa C MeSH
• vápníkové kanály - typ L MeSH
• vápníkové kanály - typ T MeSH