Experience of experimental modelling of Huntington’s disease

Stavrovskaya, A. V.; Воронков, Д. Н.; Yamshchikova, N. G.; Ol’shanskiy, A. S.; Khudoerkov, R. M.; Иллариошкин, С. Н.

doi:10.1134/s0362119716080120

Cited by 5 publications

(3 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For instance, pentylenetetrazol is widely employed to model epilepsy (1), while mitochondrial impairment in neurodegenerative diseases is often modeled by exposure of animals to inhibitors of the respiratory chain (2,3). The high sensitivity of mitochondrial complex II to inhibition by malonate and 3-nitropropionic acid (3-NP) is used to model Huntington's disease (2,4). Bioactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to its toxic 1-methyl-4-phenylpyridinium cation by glial monoamine oxidase B (5) may contribute to Parkinson'sdisease-like localization of the damage, making this inhibitor of complex I useful to create the disease models (6).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of 2-Oxoglutarate Dehydrogenase as a Chemical Model of Acute Hypobaric Hypoxia

2021

View full text Add to dashboard Cite

Both hypoxia and inhibition of 2-oxoglutarate dehydrogenase complex (OGDHC) are known to change cellular amino acid pools, but the quantitative comparison of the metabolic and physiological outcomes has not been done. We hypothesize that OGDHC inhibition models metabolic changes caused by hypoxia, as both perturb the respiratory chain function, limiting either the NADH (OGDHC inhibition) or oxygen (hypoxia) supply. In the current study, we quantify the changes in the amino acid metabolism after OGDHC inhibition in the highly sensitive to hypoxia cerebellum and compare them to the earlier characterized changes after acute hypobaric hypoxia. In addition, the associated physiological effects are characterized and compared. A specific OGDHC inhibitor succinyl phosphonate (SP) is shown to act similar to hypoxia, increasing levels of many amino acids in the cerebellum of non-pregnant rats, without affecting those in the pregnant rats. Compared with hypoxia, stronger effects of SP in non-pregnant rats are observed on the levels of cerebellar amino acids, electrocardiography (ECG), and freezing time. In pregnant rats, hypoxia affects ECG and behavior more than SP, although none of the stressors significantly change the levels of cerebellar amino acids. The biochemical differences underlying the different physiological actions of SP and hypoxia are revealed by correlation analysis of the studied parameters. The negative correlations of cerebellar amino acids with OGDHC and/or tryptophan, shown to arise after the action of SP and hypoxia, discriminate the overall metabolic action of the stressors. More negative correlations are induced in the non-pregnant rats by hypoxia, and in the pregnant rats by SP. Thus, our findings indicate that the OGDHC inhibition mimics the action of acute hypobaric hypoxia on the cerebellar amino acid levels, but a better prediction of the physiological outcomes requires assessment of integral network changes, such as increases in the negative correlations among the amino acids, OGDHC, and/or tryptophan.

show abstract

Section: Introductionmentioning

confidence: 99%

Inhibition of 2-Oxoglutarate Dehydrogenase as a Chemical Model of Acute Hypobaric Hypoxia

2021

View full text Add to dashboard Cite

show abstract

“…Injection of 3-NP to rats is considered as a well-established experimental model of HD. When given systemically, 3-NP can easily cross the BBB [ 41 ] and cause bilateral striata lesions [ 42 ] and therefore, mimics the symptoms and neuropathology of HD in humans [ 43 – 45 ]. Herein, 3-NP intoxication resulted in diminished locomotor activity and loss of grip strength as proved by the results of the open field and grip strength tests, indicating motor impairment and striatal neurodegeneration, like that established in the late stages in HD patients [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Azilsartan Attenuates 3-Nitropropinoic Acid-Induced Neurotoxicity in Rats: The Role of IĸB/NF-ĸB and KEAP1/Nrf2 Signaling Pathways

Hamouda,

Sayed,

Eid

et al. 2024

Neurochem Res

View full text Add to dashboard Cite

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by motor, psychiatric and cognitive symptoms. Injection of 3-nitropropionic acid (3-NP) is a widely used experimental model for induction of HD. The current study aimed to inspect the potential neuroprotective properties of azilsartan (Azil), an angiotensin II type 1 receptor blocker (ATR1), in 3-NP-induced striatal neurotoxicity in rats. Rats were randomly allocated into five groups and treated for 14 days as follows: group I received normal saline; group II received Azil (10 mg/kg, p.o.); group III received 3-NP (10 mg/kg, i.p); group IV and V received Azil (5 or 10 mg/kg, p.o, respectively) 1 h prior to 3-NP injection. Both doses of Azil markedly attenuated motor and behavioural dysfunction as well as striatal histopathological alterations caused by 3-NP. In addition, Azil balanced striatal neurotransmitters levels as evidenced by the increase of striatal gamma-aminobutyric acid content and the decrease of glutamate content. Azil also amended neuroinflammation and oxidative stress via modulating IĸB/NF-ĸB and KEAP1/Nrf2 downstream signalling pathways, as well as reducing iNOS and COX2 levels. Moreover, Azil demonstrated an anti-apoptotic activity by reducing caspase-3 level and BAX/BCL2 ratio. In conclusion, the present study reveals the neuroprotective potential of Azil in 3-NP-induced behavioural, histopathological and biochemical changes in rats. These findings might be attributed to inhibition of ATR1/NF-κB signalling, modulation of Nrf2/KEAP1 signalling, anti-inflammatory, anti-oxidant and anti-apoptotic properties. Graphical Abstract

show abstract

“…Induce lesiones en el caudado-putamen, incrementa el EO llevando a perdida neuronal y gliosis reactiva en modelos animales tales como ratas [Beal et al, 1993] y primates [Brouillet et al, 1999;Lee & Chang, 2004]. El uso del 3-NP como un modelo farmacológico de la EH en animales tiene varias ventajas, reproduce la patofisiología observada en pacientes [Mehan et al, 2017], cruza la barrera hematoencefálica rápidamente al ser administrado sistémicamente [Stavrovskaya et al, 2016] y su principal acción ha sido relacionada con la disfunción mitocondrial, en particular con la inhibición del CII y la generación de ERO [Liot et al, 2009].…”

Section: Discussionunclassified

Inducción del factor de transcripción Nrf2 en dos contextos patológicos: Enfermedad de Huntington asociada a la edad e isquemia-reperfusión cardíaca

Palacios

View full text Add to dashboard Cite

AMPK: Cinasa activada por adenosina monofosfato (protein kinase AMP-activated) ANOVA: Análisis de varianza de una vía Atg: Proteinas relacionadas a autofagia (autophagy-related protein) ADN: Ácido desoxirribonucleico ADP: Adenosín difosfato ARE: Elemento de respuesta antioxidante (antioxidant response element) ATP: Adenosín trifosfato Buffer RIPA: Buffer de ensayo de radioinmunoprecipitación (RadioImmunoPrecipitation Assay

show abstract

Experience of experimental modelling of Huntington’s disease

Cited by 5 publications

References 35 publications

Inhibition of 2-Oxoglutarate Dehydrogenase as a Chemical Model of Acute Hypobaric Hypoxia

Inhibition of 2-Oxoglutarate Dehydrogenase as a Chemical Model of Acute Hypobaric Hypoxia

Azilsartan Attenuates 3-Nitropropinoic Acid-Induced Neurotoxicity in Rats: The Role of IĸB/NF-ĸB and KEAP1/Nrf2 Signaling Pathways

Inducción del factor de transcripción Nrf2 en dos contextos patológicos: Enfermedad de Huntington asociada a la edad e isquemia-reperfusión cardíaca

Contact Info

Product

Resources

About