Anti-apoptotic effects of valproic acid treatment on dopaminergic neuronal loss in a 6-hydroxydopamine model of Parkinson’s disease in rats

Year 2022, , 194 - 203, 24.05.2022

Alev Cumbul , Signem Eyuboglu , Elif Çiğdem Keleş , Unal Uslu , Ece Genç

https://doi.org/10.21673/anadoluklin.1062913

Abstract

Aim: Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons resulting in deterioration of motor activity in patients. Currently, available therapies including Levodopa (L-DOPA) are more geared toward the treatment of symptoms. Therefore, developing effective neuroprotective therapies is needed. Valproic acid (VPA) has shown potent neuroprotective effects on dopamine (DA) neurons in various brain regions. The aim of this study is to investigate whether VPA attenuates the neuronal loss when co-treated with L-DOPA in a 6-hydroxydopamine (6-OHDA) induced PD model in rats.

Methods: Male Wistar Albino rats received intranigral injection of 6-OHDA unilaterally. Twelve days later rats received either saline, L-DOPA, VPA, or L-DOPA+ VPA for 9 days. To determine whether rats had dopaminergic neuronal loss apomorphine-induced rotation test was used. Immunohistochemical analyses were performed in the Substantia Nigra pars compacta (SNpc) by measuring the tyrosine hydroxylase (TH) positive neurons and the apoptotic neurons.

Results: 6-OHDA injection showed clinically impairment of the motor function with histologically significant damage to the dopaminergic neurons. VPA administration combined with L- DOPA protected neurons in SNpc by increasing the TH positive neurons and by decreasing the apoptotic neurons. L-DOPA given as a monotherapy, on the other hand, was ineffective on these parameters.

Conclusion: Our experiments demonstrated that VPA had a neuroprotective effect when used with L-DOPA in the PD rat model.

Keywords

apoptosis;, Parkinson’s disease, rat model, tyrosine hydroxylase, valproic acid, 6-hydroxydopamine

Supporting Institution

Yeditepe Üniversitesi

Project Number

120800002

Thanks

We would like to thank Dr. Aikaterini Panteli and Architect Ezgi Güven for their valuable support in the study.

Sıçanlarda 6-hidroksidopamin modeli ile oluşturulan Parkinson hastalığında valproik asit tedavisinin dopaminerjik nöronal kayıp üzerindeki anti-apoptotik etkileri

Abstract

Amaç: Parkinson hastalığı (PH), hastalarda motor aktivitede bozulma ile sonuçlanan dopaminerjik nöronların ilerleyici kaybı ile karakterizedir. Levodopa (L-DOPA) dâhil olmak üzere mevcut tedaviler daha çok semptomların tedavisine yöneliktir. Bu nedenle, etkili nöroprotektif tedavilerin geliştirilmesine ihtiyaç vardır. Valproik asit (VPA), çeşitli beyin bölgelerindeki dopamin (DA) nöronları üzerinde güçlü nöroprotektif etkiler göstermiştir. Bu çalışmanın amacı, sıçanlarda 6-hidroksidopamin (6-OHDA) ile indüklenen PH modelinde VPA’nın L-DOPA ile birlikte tedavi edildiğinde nöronal kaybı azaltıp azaltmadığını araştırmaktır.

Yöntemler: Erkek Wistar Albino sıçanlarına tek taraflı olarak intranigral 6-OHDA enjeksiyonu yapıldı. On iki gün sonra sıçanlara, 9 gün boyunca salin, L-DOPA, VPA veya L-DOPA+ VPA verildi. Sıçanlarda dopaminerjik nöron kaybı olup olmadığını belirlemek için apomorfin kaynaklı rotasyon testi kullanıldı. Substantia Nigra pars compacta’da (SNpc) tirozin hidroksilaz (TH) pozitif nöronlar ve apoptotik nöronlar ölçümleri için immünohistokimyasal analizler yapıldı.

Bulgular: 6-OHDA enjeksiyonu, klinik motor fonksiyon bozukluğu ve dopaminerjik nöronlarda önemli hasar gösterdi. VPA tedavisi, TH pozitif nöronları artırarak ve apoptotik nöronları azaltarak SNpc’deki nöronları korumuştur. L-DOPA ise bu parametreler üzerinde etkisizdi.

Sonuç: Deneylerimiz, PH sıçan modelinde L-DOPA ile birlikte kullanıldığında VPA’nın nöroprotektif bir etkiye sahip olduğunu göstermiştir.

Keywords

apoptoz;, Parkinson hastalığı, sıçan modeli, tirozin hidroksilaz, valproik asit, 6-hidroksidopamin

Project Number

120800002

References

• de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol. 2006;5(6):525-35.
• Huh E, Choi JG, Sim Y, Oh MS. An Integrative Approach to Treat Parkinson's Disease: Ukgansan Complements LDopa by Ameliorating Dopaminergic Neuronal Damage and L-Dopa-Induced Dyskinesia in Mice. Front Aging Neurosci. 2019;10:431.
• Hinz M, Stein A, Cole T. Parkinson's disease: carbidopa, nausea, and dyskinesia [retracted in: Clin Pharmacol. 2021 Mar 03;13:43]. Clin Pharmacol. 2014;6:189-94.
• Iwaki H, Nishikawa N, Nagai M, Tsujii T, Yabe H, Kubo M, et al. Pharmacokinetics of levodopa/benserazide versus levodopa/carbidopa in healthy subjects and patients with Parkinson’s disease. Neurol Clin Neurosci. 2015;3(2):68–73.
• Kidd SK, Schneider JS. Protective effects of valproic acid on the nigrostriatal dopamine system in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neuroscience. 2011;194:189–94.
• Berger SL. The complex language of chromatin regulation during transcription. Nature. 2007;447(7143):407–12.
• Sharma S, Taliyan R. Targeting histone deacetylases: a novel approach in Parkinson’s disease. Parkinsons Dis. 2015;2015:303294.
• Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, et al. RAS/ERK signaling promotes sitespecific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem. 2007;282(19):14056-64.
• Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 4th ed. San Diego, CA: Academic Press; 1998.
• Huh E, Choi JG, Sim Y, Oh MS. An Integrative Approach to Treat Parkinson’s Disease: Ukgansan Complements LDopa by Ameliorating Dopaminergic Neuronal Damage and L-Dopa-Induced Dyskinesia in Mice. Front Aging Neurosci. 2019;10:431.
• Tayarani-Binazir KA, Jackson MJ, Strang I, Jairaj M, Rose S, Jenner P. Benserazide dosing regimen affects the response to L-3,4-dihydroxyphenylalanine in the 6-hydroxydopamine-lesioned rat. Behav Pharmacol. 2012;23(2):126-33.
• Ungerstedt U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol. 1968;5(1):107-10.
• Kohen MC, Tatlipinar S, Cumbul A, Uslu Ü. The effects of bevacizumab treatment in a rat model of retinal ischemia and perfusion injury. Mol Vis. 2018;24:239-50.
• Jackson-Lewis V, Blesa J, Przedborski S. Animal models of Parkinson's disease. Parkinsonism Relat Disord. 2012;18 Suppl 1:S183-5.
• Glinka Y, Tipton KF, Youdim MB. Nature of inhibition of mitochondrial respiratory complex I by 6-Hydroxydopamine. J Neurochem. 1996;66(5):2004-10.
• Björklund A, Dunnett SB. The Amphetamine Induced Rotation Test: A Re-Assessment of Its Use as a Tool to Monitor Motor Impairment and Functional Recovery in Rodent Models of Parkinson's Disease. J Parkinsons Dis. 2019;9(1):17-29.
• Lv L, Sun Y, Han X, Xu CC, Tang YP, Dong Q. Valproic acid improves outcome after rodent spinal cord injury: potential roles of histone deacetylase inhibition. Brain Res. 2011;1396:60-8.
• Sriram A, Ward HE, Hassan A, et al. Valproate as a treatment for dopamine dysregulation syndrome (DDS) in Parkinson's disease. J Neurol. 2013;260(2):521-7.
• Mahmoud F, Tampi RR. Valproic acid-induced parkinsonism in the elderly: a comprehensive review of the literature. Am J Geriatr Pharmacother. 2011;9(6):405-12.
• Palese F, Pontis S, Realini N, Piomelli D. A protective role for N-acylphosphatidylethanolamine phospholipase D in 6-OHDA-induced neurodegeneration. Sci Rep. 2019;9(1):15927.
• Cebrián C, Sulzer D. Neuroinflammation as a potential mechanism underlying parkinsons disease. In: Verstreken P, editor. Parkinson’s Disease. Elsevier; 2017. p.245–79.
• Dagdelen M, Cumbul A, Uslu Ü, Genç E. Apoptosis in a 6-hydroxydopamine rat model of Parkinson’s disease: impact of valproic acid. Eur Neuropsychopharmacol . 2014;24 Suppl 2:241.
• Ballif BA, Blenis J. x. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 2001;12(8):397–408.