Sirtuins and Neuropeptide y downregulation in Flinders Sensitive Line Rat Model of Depression

Abstract Objective: Since the NAD+-dependent histone deacetylases sirtuin-1 (SIRT1) and sirtuin-2 (SIRT2) are critically involved in epigenetics, endocrinology and immunology and affect the longevity in model organisms, we investigated their expression in brains of 3 month old and 14-15 month old rat model of depression Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats. In view of the dysregulated NPY system in depression we also studied NPY in young and old FSL to explore the temporal trajectory of depressive-like-ageing interaction. Methods: Sirt1, Sirt2 and Npy mRNA were determined using qRT-PCR in prefrontal cortex (PFC) from young and old FSL and FRL, and in hippocampi from young FSL and FRL. Results: PFC. Sirt1 expression was decreased in FSL (p=0.001). An interaction between age and genotype was found (p=0.032); young FSL had lower Sirt1 with respect to both age (p=0.026) and genotype (p=0.001). Sirt2 was lower in FSL (p=0.003). Npy mRNA was downregulated in FSL (p=0.001) but did not differ between the young and old rat groups. Hippocampus.Sirt1 was reduced in young FSL compared to young FRL (p=0.005). There was no difference in Sirt2 between FSL and FRL. Npy levels were decreased in hippocampus of young FSL compared to young FRL (p=0.003). Effects of ageing could not be investigated due to loss of samples. Conclusions: i. This is the first demonstration that SIRT1 and SIRT2 are changed in brain of FSL, a rat model of depression ; ii. The changes are age dependent; iii. Sirtuins are potential targets for treatment of age-related neurodegenerative diseases.

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Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression

Progress in Neuro-Psychopharmacology and Biological Psychiatry ◽

10.1016/j.pnpbp.2010.05.029 ◽

2010 ◽

Vol 34 (6) ◽

pp. 1075-1084 ◽

Cited By ~ 8

Author(s):

Olga Kotsovolou ◽

Magnus Ingelman-Sundberg ◽

Matti A. Lang ◽

Marios Marselos ◽

David H. Overstreet ◽

...

Keyword(s):

Rat Model ◽

Hepatic Drug ◽

Sensitive Line ◽

Flinders Sensitive Line

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Gene expression related to serotonergic and glutamatergic neurotransmission is altered in the flinders sensitive line rat model of depression: Effect of ketamine

Synapse ◽

10.1002/syn.21940 ◽

2016 ◽

Vol 71 (1) ◽

pp. 37-45 ◽

Cited By ~ 4

Author(s):

Kristian Gaarn Du Jardin ◽

Heidi Kaastrup Müller ◽

Connie Sanchez ◽

Gregers Wegener ◽

Betina Elfving

Keyword(s):

Gene Expression ◽

Rat Model ◽

Glutamatergic Neurotransmission ◽

Depression Effect ◽

Sensitive Line ◽

Flinders Sensitive Line

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Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression

Neurochemical Research ◽

10.1007/s11064-015-1719-6 ◽

2015 ◽

Vol 40 (11) ◽

pp. 2293-2303

Author(s):

Helene Blanchard ◽

Lisa Chang ◽

Amir H. Rezvani ◽

Stanley I. Rapoport ◽

Ameer Y. Taha

Keyword(s):

Arachidonic Acid ◽

Rat Model ◽

Acid Incorporation ◽

Sensitive Line ◽

Flinders Sensitive Line

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Noninvasive quantification of SIRT1 expression–activity and pharmacologic inhibition in a rat model of intracerebral glioma using 2-[18F]BzAHA PET/CT/MRI

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa006 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Maxwell T Laws ◽

Robin E Bonomi ◽

David J Gelovani ◽

Jeremy Llaniguez ◽

Xin Lu ◽

...

Keyword(s):

Rat Model ◽

Histone Deacetylases ◽

Quantitative Imaging ◽

Specific Inhibitor ◽

Sirtuin 1 ◽

Sprague Dawley ◽

Sirt1 Expression ◽

Pet Ct ◽

Expression Activity ◽

Pharmacologic Inhibition

Abstract Background Several studies demonstrated that glioblastoma multiforme progression and recurrence is linked to epigenetic regulatory mechanisms. Sirtuin 1 (SIRT1) plays an important role in glioma progression, invasion, and treatment response and is a potential therapeutic target. The aim of this study is to test the feasibility of 2-[18F]BzAHA for quantitative imaging of SIRT1 expression–activity and monitoring pharmacologic inhibition in a rat model of intracerebral glioma. Methods Sprague Dawley rats bearing 9L (N = 12) intracerebral gliomas were injected with 2-[18F]BzAHA (300–500 µCi/animal i.v.) and dynamic positron-emission tomography (PET) imaging was performed for 60 min. Then, SIRT1 expression in 9L tumors (N = 6) was studied by immunofluorescence microscopy (IF). Two days later, rats with 9L gliomas were treated either with SIRT1 specific inhibitor EX-527 (5 mg/kg, i.p.; N = 3) or with histone deacetylases class IIa specific inhibitor MC1568 (30 mg/kg, i.p.; N = 3) and 30 min later were injected i.v. with 2-[18F]BzAHA. PET-computerized tomography-magnetic resonance (PET/CT/MR) images acquired after EX-527 and MC1568 treatments were co-registered with baseline images. Results Standard uptake values (SUVs) of 2-[18F]BzAHA in 9L tumors measured at 20 min post-radiotracer administration were 1.11 ± 0.058 and had a tumor-to-brainstem SUV ratio of 2.73 ± 0.141. IF of 9L gliomas revealed heterogeneous upregulation of SIRT1, especially in hypoxic and peri-necrotic regions. Significant reduction in 2-[18F]BzAHA SUV and distribution volume in 9L tumors was observed after administration of EX-527, but not MC1568. Conclusions PET/CT/MRI with 2-[18F]BzAHA can facilitate studies to elucidate the roles of SIRT1 in gliomagenesis and progression, as well as to optimize therapeutic doses of novel SIRT1 inhibitors.

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Altered fecal microbiota composition in the Flinders sensitive line rat model of depression

Psychopharmacology ◽

10.1007/s00213-018-5094-2 ◽

2018 ◽

Vol 236 (5) ◽

pp. 1445-1457 ◽

Cited By ~ 13

Author(s):

Sandra Tillmann ◽

Anders Abildgaard ◽

Gudrun Winther ◽

Gregers Wegener

Keyword(s):

Rat Model ◽

Fecal Microbiota ◽

Microbiota Composition ◽

Sensitive Line ◽

Flinders Sensitive Line

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Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat

Acta Neuropsychiatrica ◽

10.1017/neu.2019.15 ◽

2019 ◽

Vol 31 (04) ◽

pp. 213-219 ◽

Cited By ~ 7

Author(s):

Oskar Jefsen ◽

Kristoffer Højgaard ◽

Sofie Laage Christiansen ◽

Betina Elfving ◽

David John Nutt ◽

...

Keyword(s):

Locomotor Activity ◽

Rat Model ◽

Serotonin Receptor ◽

Therapeutic Potential ◽

Forced Swim Test ◽

Psychiatric Illnesses ◽

Immobility Time ◽

Sensitive Line ◽

Behavioural Tests ◽

Flinders Sensitive Line

AbstractObjective:Psilocybin is a serotonin receptor agonist with a therapeutic potential for treatment-resistant depression and other psychiatric illnesses. We investigated whether the administration of psilocybin had an antidepressant-like effect in a rat model of depression.Methods:Using the Flinders Sensitive Line (FSL) rat model of depression, we assessed the antidepressant-like effect of psilocin and psilocybin, measured as a reduction in immobility time in the forced swim test (FST). We measured locomotor activity in an open field test (OFT) to control for stimulant properties of the drugs. We performed a set of experiments to test different doses, treatment paradigms, and timing of the tests in relation to the drug administration.Results:Psilocin and psilocybin showed no effect on immobility, struggling, or swimming behaviour in the FST and no effect on locomotor activity in the OFT. FSL rats did show significantly more immobility than their control strain, the Flinders Resistant Line, as expected.Conclusion:Psilocin and psilocybin showed no antidepressant-like effect in the FSL rats, despite a positive effect in humans. This suggests that other animal models of depression and other behavioural tests may be more appropriate for translational studies in the effects of psilocybin.

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