Kisspeptin-54 Ameliorates Electrocardiographic Abnormalities in an Experimental Parkinson's Rat Model
Öz
Aim: Cardiac complications may arise in association with Parkinson’s disease as age progresses. Kisspeptins are a group of peptides that mediate their physiological functions by binding to the GPR54 receptor. This study aimed to investigate whether KP-54 has an effect on the electrical activity of the heart in an animal model of Parkinson's disease.
Material and Method: Sprague-Dawley rats weighing between 290–310 g were used. An experimental hemiparkinsonian rat model was generated via stereotaxic injection of the neurotoxin 6-OHDA into the right medial forebrain bundle, effectively replicating unilateral dopaminergic neuronal loss. Rats received either control (aCSF, 5 µL, ICV) or KP-54 (3 nmol/kg, ICV) treatment once daily for seven consecutive days. At the end of the seventh day, behavioral tests were conducted on the rats. Following the behavioral tests, electrocardiographic (ECG) recordings were obtained.
Results: 6-OHDA significantly increased catalepsy time (p<0.001), which was effectively reduced by KP-54 (p<0.05). In the open field test (OFT), rats injected with 6-OHDA showed decreased distance traveled (p<0.001) and velocity (p<0.01) compared to controls, whereas KP-54 treatment partially improved these motor impairments (p<0.01). ECG data revealed that the heart rate (HR), impaired following 6-OHDA administration (p<0.01), returned to control levels in the 6-OHDA + KP-54 group (p<0.01). There were no notable differences between the groups regarding P duration, PR and QRS interval. However, the QT and QTc intervals were significantly increased (p<0.01) in the Parkinson’s group and were normalized to control levels in the 6-OHDA + KP-54 group (p<0.05). These findings indicate that KP-54 corrected the QT prolongation induced by 6-OHDA.
Conclusion: In conclusion, the present findings suggest that alterations in HR and prolongation of the QT interval observed in Parkinson's disease could be prevented by the neuropeptide kisspeptin. Nevertheless, further research involving different administration routes is required to validate and expand upon these results.
Anahtar Kelimeler
Etik Beyan
All experimental procedures were conducted in accordance with institutional and international guidelines for animal care and were approved by the Akdeniz University Faculty of Medicine Animal Ethics Committee (Approval No. 1689/2024.04.002, Decision date: 15.04.2024).
Destekleyen Kurum
This study was not supported by any institution.
Teşekkür
The authors would like to thank Akdeniz University Faculty of Medicine, Department of Biophysics, for providing the infrastructure necessary for conducting the experiments.
Kaynakça
- Luo Y, Qiao L, Li M, et al. Global, regional, national epidemiology and trends of Parkinson’s disease from 1990 to 2021: findings from the Global Burden of Disease Study 2021. Front Aging Neurosci. 2025;16:1498756.
- Zafar S, Yaddanapudi SS. Parkinson disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Updated 2023 Aug 7.
- Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5.
- Pfeiffer RF. Autonomic dysfunction in Parkinson's disease. Expert Rev Neurother. 2012;12:697-706.
- Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update. 2014;20:485-500.
- Hu K-L, Chen Z, Li X, et al. Advances in clinical applications of kisspeptin-GnRH pathway in female reproduction. Reprod Biol Endocrinol. 2022;20:81.
- d'Anglemont de Tassigny X, Jayasena C, Murphy KG, et al. Mechanistic insights into the more potent effect of KP-54 compared to KP-10 in vivo. PLoS One. 2017;12:e0176821.
- Ramaesh T, Logie JJ, Roseweir AK, et al. Kisspeptin-10 inhibits angiogenesis in human placental vessels ex vivo and endothelial cells in vitro. Endocrinology. 2010;151:5927-34.
- Sawyer I, Smillie S-J, Bodkin JV, et al. The vasoactive potential of kisspeptin-10 in the peripheral vasculature. PLoS One. 2011;6:e14671.
- Watanabe T, Sato K. Roles of the kisspeptin/GPR54 system in pathomechanisms of atherosclerosis. Nutr Metab Cardiovasc Dis. 2020;30:889-95.
- Sinen O, Sinen AG, Derin N, Aslan MA. Nasal application of kisspeptin-54 mitigates motor deficits by reducing nigrostriatal dopamine loss in hemiparkinsonian rats. Behav Brain Res. 2024;468:115035.
- Bazett H. An analysis of the time‐relations of electrocardiograms. Annals of Noninvasive Electrocardiology. 1997;2:177-94.
- Simon C, Soga T, Parhar I. Kisspeptin-10 Mitigates α-synuclein-mediated mitochondrial apoptosis in SH-SY5Y-derived neurons via a kisspeptin receptor-independent manner. Int J Mol Sci. 2023;24:6056.
- Csabafi K, Jászberényi M, Bagosi Z, et al. Effects of kisspeptin-13 on the hypothalamic-pituitary-adrenal axis, thermoregulation, anxiety and locomotor activity in rats. Behav Brain Res. 2013;241:56-61.
- Sinen O, Sinen AG, Derin N, Aslan MA. Chronic nasal administration of kisspeptin-54 regulates mood-related disorders via amygdaloid GABA in hemi-parkinsonian rats. Balkan Med J. 2024;41:476-83.
- Chen Z, Li G, Liu J. Autonomic dysfunction in Parkinson’s disease: Implications for pathophysiology, diagnosis, and treatment. Neurobiol Dis. 2020;134:104700.
- Cuenca-Bermejo L, Almela P, Navarro-Zaragoza J, et al. Cardiac changes in Parkinson’s disease: lessons from clinical and experimental evidence. Int J Mol Sci. 2021;22:13488.
- Akbilgic O, Kamaleswaran R, Mohammed A, et al. Electrocardiographic changes predate Parkinson’s disease onset. Sci Rep. 2020;10:11319.
- Zhong L-L, Song Y-Q, Ju K-J, et al. Electrocardiogram characteristics of different motor types of Parkinson’s disease. Int J Gen Med. 2021:1057-61.
- Malkiewicz JJ, Malkiewicz M, Siuda J. Prevalence of QTc prolongation in patients with Parkinson’s disease. Assessment of the effects of drugs, clinical risk factors and used correction formula. J Clin Med. 2021;10:1396.
- Oka H, Mochio S, Sato H, Katayama K. Prolongation of QTc interval in patients with Parkinson’s disease. Eur Neurol. 1997;37:186-9.
- Terse PS, Peggins J, Seminara SB. Safety evaluation of KP-10 (Metastin 45–54) following once daily intravenous administration for 14 days in dog. Int J Toxicol. 2021;40:337-43.
- Nijher GM, Chaudhri OB, Ramachandran R, et al. The effects of kisspeptin‐54 on blood pressure in humans and plasma kisspeptin concentrations in hypertensive diseases of pregnancy. Br J Clin Pharmacol. 2010;70:674-81.
- Maguire JJ, Kirby HR, Mead EJ, et al. Inotropic action of the puberty hormone kisspeptin in rat, mouse and human: cardiovascular distribution and characteristics of the kisspeptin receptor. PloS One. 2011;6:e27601.
Öz
Kaynakça
- Luo Y, Qiao L, Li M, et al. Global, regional, national epidemiology and trends of Parkinson’s disease from 1990 to 2021: findings from the Global Burden of Disease Study 2021. Front Aging Neurosci. 2025;16:1498756.
- Zafar S, Yaddanapudi SS. Parkinson disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Updated 2023 Aug 7.
- Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5.
- Pfeiffer RF. Autonomic dysfunction in Parkinson's disease. Expert Rev Neurother. 2012;12:697-706.
- Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update. 2014;20:485-500.
- Hu K-L, Chen Z, Li X, et al. Advances in clinical applications of kisspeptin-GnRH pathway in female reproduction. Reprod Biol Endocrinol. 2022;20:81.
- d'Anglemont de Tassigny X, Jayasena C, Murphy KG, et al. Mechanistic insights into the more potent effect of KP-54 compared to KP-10 in vivo. PLoS One. 2017;12:e0176821.
- Ramaesh T, Logie JJ, Roseweir AK, et al. Kisspeptin-10 inhibits angiogenesis in human placental vessels ex vivo and endothelial cells in vitro. Endocrinology. 2010;151:5927-34.
- Sawyer I, Smillie S-J, Bodkin JV, et al. The vasoactive potential of kisspeptin-10 in the peripheral vasculature. PLoS One. 2011;6:e14671.
- Watanabe T, Sato K. Roles of the kisspeptin/GPR54 system in pathomechanisms of atherosclerosis. Nutr Metab Cardiovasc Dis. 2020;30:889-95.
- Sinen O, Sinen AG, Derin N, Aslan MA. Nasal application of kisspeptin-54 mitigates motor deficits by reducing nigrostriatal dopamine loss in hemiparkinsonian rats. Behav Brain Res. 2024;468:115035.
- Bazett H. An analysis of the time‐relations of electrocardiograms. Annals of Noninvasive Electrocardiology. 1997;2:177-94.
- Simon C, Soga T, Parhar I. Kisspeptin-10 Mitigates α-synuclein-mediated mitochondrial apoptosis in SH-SY5Y-derived neurons via a kisspeptin receptor-independent manner. Int J Mol Sci. 2023;24:6056.
- Csabafi K, Jászberényi M, Bagosi Z, et al. Effects of kisspeptin-13 on the hypothalamic-pituitary-adrenal axis, thermoregulation, anxiety and locomotor activity in rats. Behav Brain Res. 2013;241:56-61.
- Sinen O, Sinen AG, Derin N, Aslan MA. Chronic nasal administration of kisspeptin-54 regulates mood-related disorders via amygdaloid GABA in hemi-parkinsonian rats. Balkan Med J. 2024;41:476-83.
- Chen Z, Li G, Liu J. Autonomic dysfunction in Parkinson’s disease: Implications for pathophysiology, diagnosis, and treatment. Neurobiol Dis. 2020;134:104700.
- Cuenca-Bermejo L, Almela P, Navarro-Zaragoza J, et al. Cardiac changes in Parkinson’s disease: lessons from clinical and experimental evidence. Int J Mol Sci. 2021;22:13488.
- Akbilgic O, Kamaleswaran R, Mohammed A, et al. Electrocardiographic changes predate Parkinson’s disease onset. Sci Rep. 2020;10:11319.
- Zhong L-L, Song Y-Q, Ju K-J, et al. Electrocardiogram characteristics of different motor types of Parkinson’s disease. Int J Gen Med. 2021:1057-61.
- Malkiewicz JJ, Malkiewicz M, Siuda J. Prevalence of QTc prolongation in patients with Parkinson’s disease. Assessment of the effects of drugs, clinical risk factors and used correction formula. J Clin Med. 2021;10:1396.
- Oka H, Mochio S, Sato H, Katayama K. Prolongation of QTc interval in patients with Parkinson’s disease. Eur Neurol. 1997;37:186-9.
- Terse PS, Peggins J, Seminara SB. Safety evaluation of KP-10 (Metastin 45–54) following once daily intravenous administration for 14 days in dog. Int J Toxicol. 2021;40:337-43.
- Nijher GM, Chaudhri OB, Ramachandran R, et al. The effects of kisspeptin‐54 on blood pressure in humans and plasma kisspeptin concentrations in hypertensive diseases of pregnancy. Br J Clin Pharmacol. 2010;70:674-81.
- Maguire JJ, Kirby HR, Mead EJ, et al. Inotropic action of the puberty hormone kisspeptin in rat, mouse and human: cardiovascular distribution and characteristics of the kisspeptin receptor. PloS One. 2011;6:e27601.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | İnsan Biyofiziği, Tıp Fiziği |
| Bölüm | Özgün Makaleler |
| Yazarlar | |
| Yayımlanma Tarihi | |
| Gönderilme Tarihi | 3 Nisan 2025 |
| Kabul Tarihi | 1 Mayıs 2025 |
| Yayımlandığı Sayı | Yıl 2025 Cilt: 7 Sayı: 3 |
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Assoc. Prof. Zülal Öner
Address: İzmir Bakırçay University, Department of Anatomy, İzmir, Turkey
Assoc. Prof. Deniz Şenol
Address: Düzce University, Department of Anatomy, Düzce, Turkey
Editors
Assoc. Prof. Serkan Öner
İzmir Bakırçay University, Department of Radiology, İzmir, Türkiye
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