Öz
AMAÇ: Demans hastalarının büyük çoğunluğu (yaklaşık %60-70) Alzheimer hastalığı (AH)’ndan muzdariptir. AH’nın ayırt edici patolojik belirtileri senil plaklar (SP'ler), nörofibriler yumaklar (NFTS), ve nörodejenerasyondur. Bu çalışmada; nörolojik anomalileri indükleyen Acetylcholine Mustard Aziridin İon (AF64A)'nın neden olduğu hasar ve bu zararın antioksidan piperin ve betain’nin tedavi edici etkisinin belirlenmesi amaçlanmıştır.
GEREÇ VE YÖNTEM: Bu çalışmada; 24 Sprague-Dawley erkek sıçan kullanılmış ve 4 grup oluşturulmuştur: Sağlıklı sıçanlardan oluşan grup 1 (kontrol, n=6); AF64A ile deneysel demans oluşturulan grup 2 (n=6), betain tedavisi yapılan grup 3 (AF64A betain, n=6) ve piperin tedavisi yapılan grup 4 (AF64A piperin, n=6). Hipokampus dokusunda mitojenle aktifleşmiş protein kinaz-1(MAPK-1) mRNA düzeyi, karaciğer ve kan serum örneklerinde Malondialdehit (MDA) düzeyleri ile karaciğer ve eritrosit örneklerinde redükte glutatyon (GSH) düzeyleri araştırılmıştır. İlaveten, morris su labirent testi kullanılarak davranışsal yönden kaynaklanan farklılıklar süre açısından belirlenmiştir.
BULGULAR: Karaciğer ve eritrositlerdeki en yüksek GSH düzeyleri piperin uygulanan grup 4’de belirlenmiştir (p<0.01). Karaciğer ve plazma MDA düzeyleri bakımından en yüksek sonuçlar grup 2’de ve en düşük sonuçlar grup 4’de kaydedilmiştir (p<0.05). Beyin doku patoloji bulgularında da en iyi sonuçlar piperin uygulanan grupta gözlenmiştir (p<0.05). Hipokampüs MAPK-1 mRNA düzeylerinde grup 2’de belirgin artış, grup 4’de ise baskılanma izlenmiştir.
SONUÇ: Belirlenen patolojik, biyokimyasal ve genetik analizler ile davranış testi sonucundaki reaksiyon süresinin uzaması göstermiştir ki, AF64A kullanılması beyin sinir hücresini önemli düzeyde tahrip etmektedir. Fakat özellikle piperin uygulamasının, betainin etkisine kıyasla, tüm negatif işaretlerin kontrol seviyesine getirilmesiyle AF64A’nın hasar verici etkisi üzerinde neredeyse geri dönüşümlü bir etki yarattığı gözlenmiştir. AF64A uygulaması, sıçanlarda önemli düzeyde beyin hasarına yol açarak Alzheimer’a benzer etki yaratmaktadır. Alternatif tedavi kapsamında betain ve piperin uygulamasının AF64A'ün tüm olumsuz sonuçlarını, ki özellikle piperin uygulaması, neredeyse tamamen normal seviyelere indirdiğini göstermektedir. Bu bulgular, demans ve özellikle AH’nda oksidan etkilerin azaltılmasında ve/veya geriletilmesinde antioksidan özellikteki piperin kullanımının faydalı olabileceği sonucunu işaret etmektedir.
Kaynakça
- Kıdd PM. Alzheimer’s Disease, Amnestic Mild Cognitive Impairment, and Age-Associated Memory Impairment: Current Understanding and Progress Toward Integrative Prevention. Altern Med Rev. 2008; 13(2): 85-115.
- Serý O, Povová J, Míšek I, Pešák L, Janout V. Molecular mechanisms of neuropathologicalchanges in Alzheimer's disease: a review. Folia Neuropathol. 2013; 51(1):1-9.
- Ferrer I. Defining Alzheimer as a common age-related neurodegenerative process not inevitably leading to dementia. Prog Neurobiol. 2012; 97: 38–51.
- Fargo K, Bleıler L. Alzheimer’s Association Report 2014 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia. 2014; 10 (2014): 47-92.
- Ferreıra D, Perestelo-pérez L, Westman E, Wahlund LO, Sarría A, Serrano-aguılar P. Meta-Review of CSF Core Biomarkers in Alzheimer'sDisease: The State-of-the-Artafter the New Revised Diagnostic Criteria. Front Aging Neurosci. 2014; 6: 47.
- Blennow K, Leon MJD, Zetterberg H. Alzheimer’s disease. Lancet. 2006; 368: 387–403.
- Schellenberg GD, Montıne TJ. The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathol 2012; 124: 305–323.
- Munoz L, Ammıt AJ. Targeting p38 MAPK pathway for the treatment of Alzheimer's disease. Neuropharmacology. 2010; 58(3): 561–568.
- Pımplıkar SW. Neuroinflammation in Alzheimer's disease: from pathogenesis to a therapeutic target. J Clin Immunol. 2014; 34(1): 64-69. DOI 10. 1007/ s10875-014-0032-5.
- Hanın I. The AF64A Model of cholınergic hypofunctıon: An Update. Life Sci. 1996; 58(22): 1955-1964.
- Hıramatsu M, Yamatsu T, Kameyama T, Nabeshima T. Effects of repeated administration of (˗)-nicotine on AF64A-induced learning and memory impairment in rats. J Neural Transm. 2002; 109: 361–375.
- Rose M, Dudas B, Cornellı U, Hanın I. Glycosaminoglycan C3 protects against AF64A-induced cholinotoxicity in a dose-dependent and time-dependent manner. Brain Research. 2004; 1015: 96–102.
- Obeıd R, Herrmann W. Homocysteine and lipids: S-Adenosyl methionine as a key intermediate. FEBS Letters. 2009; 583: 1215–1225.
- Zhang Y, Zhu T, Wang L, Pan Y-H, Zhang S. Homocysteine Homeostasis and Betaine-Homocysteine S-Methyltransferase Expression in the Brain of Hibernating Bats. PLoS ONE. 2013; 8(12): e85632. doi:10.1371/journal.pone. 0085632.
- Lawson-yuen A, Levy HL. The use of betaine in the treatment of elevated homocysteine. Mol Genet Metab. 2006; 88: 201–207.
- Srınıvasan K. Black Pepper and its Pungent Principle-Piperine: A Review of Diverse Physiological Effects. Crit Rev Food Sci Nutr. 2007; 47(8): 735-748.
- Moghadamnıa AA, Zangoorı V, Zargar-nattaj SS, Tayebı P, Moghadamnıa Y, Jorsarae SGA. Effect of breastfeeding piperine on the learning of offspring mice: interaction with caffeine and diazepam. J Exp Pharmacol. 2010; 2010(2): 111–120.
- Butt MS, Pasha I, Sultan MT, Randhawa MA, Saeed F, Ahmed W. Black pepper and health claims: A comprehensive treatise. Crit Rev Food Sci Nutr. 2013; 53(9): 875-886.
- Gallagher M, Burwell R, & Burchinal MR. Severity of spatial learning impairment in aging: development of a learning index for performance in the Morris water maze. Behavioral neuroscience. 1993; 107(4): 618-626.
- Arslan S, Ateş E, Atikcan DT, Uyanık E, & Yapar C. Stres Altında Olan Sıçanlarda Ve Normal Koşullardaki Sıçanlarda Antidepresan “Fluoksetin Hidroklorür Kullanımının Öğrenme Üzerine Etkileri. Erişim:http://tip.baskent.edu.tr/egitim/mezuniyetoncesi/calismagrp/ogrsmpzsnm13/13.S14.pdf] 2013.
- Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Research. 2001; Vol 29 (9): e45.
- Yu L, Wang S, Chen X, Yang H, Li X, Xu Y, et al. Orientin alleviates cognitive deficits and oxidative stress in Aβ1-42-induced mouse model of Alzheimer's disease. Life Sci. 2015; 15(121): 104-9.
- Pannangrong W1, Wattanathorn J, Muchimapura S, Tiamkao S, Tong-un T. Purple rice berry is neuroprotective and enhances cognition in a rat model of Alzheimer's disease. J Med Food. 2011; 14(7-8): 688-94. doi: 10.1089/jmf.2010.1312.
- Gulyaeva NV, Lazareva NA, Libe ML, Mıtrokhına OS, Onufrıev MV, Stepanıchev MYu, et al. Oxidative stress in the brain following intraventricular administration of ethylcholine aziridinium (AF64A). Brain Res. 1996; 726(1-2):174-80.
- Bachurın S, Bukatına E, Lermontova N, Tkachenko S, Afanasıev A, Grıgorıev V, et al. Antihistamine Agent Dimebon As a Novel Neuroprotector and a Cognition Enhancer. Ann NY Acad Sci. 2001; 939: 425-35.
- Bachurın S, Oxenkrug G, Lermontova N, Afanasıev A, Beznosko B, Vankin G, et al. N-Acetylserotonin, Melatonin and Their Derivatives Improve Cognition and Protect against -Amyloid-Induced Neurotoxicity. Ann NY Acad Sci. 1999; 890:155-66.
- Chonpathompikunlert P1, Wattanathorn J, Muchimapura S. Piperine, the main alkaloid of Thai black pepper, protects against neurodegeneration and cognitive impairment in animal model of cognitive deficit like condition of Alzheimer's disease. Food Chem Toxicol. 2010; 48(3): 798-802. doi: 10.1016/j.fct.2009.12.009. Yamada K1, Furukawa S, Iwasaki T, Ichitani Y. Nicotine improves AF64A-induced spatial memory deficits in Morris water maze in rats. Neurosci Lett. 2010; 469(1): 88-92. doi: 10.1016/j.neulet.2009.11.050.
- Varga J, Klausz B, Domokos Á, Kálmán S, Pákáskı M, Szűcs S, et al. Increase in Alzheimer’s related markers preceeds memorydisturbances: Studies in vasopressin-deficient Brattleboro rat. Brain Res Bull. 2014; 100: 6-13.
Öz
OBJECTIVE: The great majority of dementia patients (about 60-70%) suffer from Alzheimer disease (AD). The distinctive pathological signs of AD are senile plaques (SPs), neurofibrillary tangles (NFTS), synaptic loss and neurodegeneration. In this study; it is aimed to determine the damage caused by Acetylcholine Mustard Aziridin Ion (AF64A), which induces neurological anomalies, and the therapeutic effect of antioxidant piperine and betaine.
MATERIAL AND METHODS: In this study; 24 Sprague-Dawley male rats were used and 4 groups were formed: Group 1 consisting of healthy rats (control, n = 6); Group 2 (n = 6) with experimental dementia induced by AF64A, group 3 (AF64A betaine, n = 6) treated with betaine and 4 (AF64A piperine, n = 6) treated with piperine. The mRNA levels of mitogen activated protein kinase-1 (MAPK-1) in hippocampus tissue, Malondialdehyde (MDA) levels in liver and blood serum samples and reduced glutathione (GSH) levels in liver and erythrocyte samples were investigated. In addition, behavioral differences were determined in terms of duration using the morris water maze test.
RESULTS: The highest GSH levels in liver and erythrocytes were determined in piperine-treated group 4 (p <0.01). The highest results were recorded in group 2 and the lowest results were recorded in group 4 (p <0.05) in terms of liver and plasma MDA levels. The best results in brain tissue pathology findings were also observed in the piperine applied group (p <0.05). There was a significant increase in hippocampus MAPK-1 mRNA levels in group 2 whereas a decrease in group 4.
CONCLUSIONS:Determined pathological, biochemical and genetic analyzes beside the longest reaction time in the behavior test result showed that the use of AF64A significantly destroys the brain nerve cell. But especially piperine treatment create almost reversible effect onto AF64A damaging act via bring down all negative signs into control level compare to the betaine effect. AF64A application causes a significant level of brain damage in rats, creating a similar effect to Alzheimer's. As an alternative treatment, it shows that the application of betaine and piperine reduces all the negative consequences of AF64A, especially the application of piperine, to almost completely normal levels. These findings indicate that the use of antioxidant piperine may be beneficial in reducing and/or regressing oxidant effects in dementia and especially in AD.
Kaynakça
- Kıdd PM. Alzheimer’s Disease, Amnestic Mild Cognitive Impairment, and Age-Associated Memory Impairment: Current Understanding and Progress Toward Integrative Prevention. Altern Med Rev. 2008; 13(2): 85-115.
- Serý O, Povová J, Míšek I, Pešák L, Janout V. Molecular mechanisms of neuropathologicalchanges in Alzheimer's disease: a review. Folia Neuropathol. 2013; 51(1):1-9.
- Ferrer I. Defining Alzheimer as a common age-related neurodegenerative process not inevitably leading to dementia. Prog Neurobiol. 2012; 97: 38–51.
- Fargo K, Bleıler L. Alzheimer’s Association Report 2014 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia. 2014; 10 (2014): 47-92.
- Ferreıra D, Perestelo-pérez L, Westman E, Wahlund LO, Sarría A, Serrano-aguılar P. Meta-Review of CSF Core Biomarkers in Alzheimer'sDisease: The State-of-the-Artafter the New Revised Diagnostic Criteria. Front Aging Neurosci. 2014; 6: 47.
- Blennow K, Leon MJD, Zetterberg H. Alzheimer’s disease. Lancet. 2006; 368: 387–403.
- Schellenberg GD, Montıne TJ. The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathol 2012; 124: 305–323.
- Munoz L, Ammıt AJ. Targeting p38 MAPK pathway for the treatment of Alzheimer's disease. Neuropharmacology. 2010; 58(3): 561–568.
- Pımplıkar SW. Neuroinflammation in Alzheimer's disease: from pathogenesis to a therapeutic target. J Clin Immunol. 2014; 34(1): 64-69. DOI 10. 1007/ s10875-014-0032-5.
- Hanın I. The AF64A Model of cholınergic hypofunctıon: An Update. Life Sci. 1996; 58(22): 1955-1964.
- Hıramatsu M, Yamatsu T, Kameyama T, Nabeshima T. Effects of repeated administration of (˗)-nicotine on AF64A-induced learning and memory impairment in rats. J Neural Transm. 2002; 109: 361–375.
- Rose M, Dudas B, Cornellı U, Hanın I. Glycosaminoglycan C3 protects against AF64A-induced cholinotoxicity in a dose-dependent and time-dependent manner. Brain Research. 2004; 1015: 96–102.
- Obeıd R, Herrmann W. Homocysteine and lipids: S-Adenosyl methionine as a key intermediate. FEBS Letters. 2009; 583: 1215–1225.
- Zhang Y, Zhu T, Wang L, Pan Y-H, Zhang S. Homocysteine Homeostasis and Betaine-Homocysteine S-Methyltransferase Expression in the Brain of Hibernating Bats. PLoS ONE. 2013; 8(12): e85632. doi:10.1371/journal.pone. 0085632.
- Lawson-yuen A, Levy HL. The use of betaine in the treatment of elevated homocysteine. Mol Genet Metab. 2006; 88: 201–207.
- Srınıvasan K. Black Pepper and its Pungent Principle-Piperine: A Review of Diverse Physiological Effects. Crit Rev Food Sci Nutr. 2007; 47(8): 735-748.
- Moghadamnıa AA, Zangoorı V, Zargar-nattaj SS, Tayebı P, Moghadamnıa Y, Jorsarae SGA. Effect of breastfeeding piperine on the learning of offspring mice: interaction with caffeine and diazepam. J Exp Pharmacol. 2010; 2010(2): 111–120.
- Butt MS, Pasha I, Sultan MT, Randhawa MA, Saeed F, Ahmed W. Black pepper and health claims: A comprehensive treatise. Crit Rev Food Sci Nutr. 2013; 53(9): 875-886.
- Gallagher M, Burwell R, & Burchinal MR. Severity of spatial learning impairment in aging: development of a learning index for performance in the Morris water maze. Behavioral neuroscience. 1993; 107(4): 618-626.
- Arslan S, Ateş E, Atikcan DT, Uyanık E, & Yapar C. Stres Altında Olan Sıçanlarda Ve Normal Koşullardaki Sıçanlarda Antidepresan “Fluoksetin Hidroklorür Kullanımının Öğrenme Üzerine Etkileri. Erişim:http://tip.baskent.edu.tr/egitim/mezuniyetoncesi/calismagrp/ogrsmpzsnm13/13.S14.pdf] 2013.
- Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Research. 2001; Vol 29 (9): e45.
- Yu L, Wang S, Chen X, Yang H, Li X, Xu Y, et al. Orientin alleviates cognitive deficits and oxidative stress in Aβ1-42-induced mouse model of Alzheimer's disease. Life Sci. 2015; 15(121): 104-9.
- Pannangrong W1, Wattanathorn J, Muchimapura S, Tiamkao S, Tong-un T. Purple rice berry is neuroprotective and enhances cognition in a rat model of Alzheimer's disease. J Med Food. 2011; 14(7-8): 688-94. doi: 10.1089/jmf.2010.1312.
- Gulyaeva NV, Lazareva NA, Libe ML, Mıtrokhına OS, Onufrıev MV, Stepanıchev MYu, et al. Oxidative stress in the brain following intraventricular administration of ethylcholine aziridinium (AF64A). Brain Res. 1996; 726(1-2):174-80.
- Bachurın S, Bukatına E, Lermontova N, Tkachenko S, Afanasıev A, Grıgorıev V, et al. Antihistamine Agent Dimebon As a Novel Neuroprotector and a Cognition Enhancer. Ann NY Acad Sci. 2001; 939: 425-35.
- Bachurın S, Oxenkrug G, Lermontova N, Afanasıev A, Beznosko B, Vankin G, et al. N-Acetylserotonin, Melatonin and Their Derivatives Improve Cognition and Protect against -Amyloid-Induced Neurotoxicity. Ann NY Acad Sci. 1999; 890:155-66.
- Chonpathompikunlert P1, Wattanathorn J, Muchimapura S. Piperine, the main alkaloid of Thai black pepper, protects against neurodegeneration and cognitive impairment in animal model of cognitive deficit like condition of Alzheimer's disease. Food Chem Toxicol. 2010; 48(3): 798-802. doi: 10.1016/j.fct.2009.12.009. Yamada K1, Furukawa S, Iwasaki T, Ichitani Y. Nicotine improves AF64A-induced spatial memory deficits in Morris water maze in rats. Neurosci Lett. 2010; 469(1): 88-92. doi: 10.1016/j.neulet.2009.11.050.
- Varga J, Klausz B, Domokos Á, Kálmán S, Pákáskı M, Szűcs S, et al. Increase in Alzheimer’s related markers preceeds memorydisturbances: Studies in vasopressin-deficient Brattleboro rat. Brain Res Bull. 2014; 100: 6-13.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Klinik Tıp Bilimleri |
| Bölüm | Makaleler-Araştırma Yazıları |
| Yazarlar | |
| Yayımlanma Tarihi | 11 Mayıs 2020 |
| Kabul Tarihi | 6 Kasım 2019 |
| Yayımlandığı Sayı | Yıl 2020 Cilt: 21 Sayı: 2 |
Kaynak Göster
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