Minocycline prevents the development of depression-like behavior and hippocampal inflammation in a rat model of Alzheimer’s disease
- 170 Downloads
Considerable clinical and experimental studies have shown that depression-related disorders are the most common neuropsychiatric symptoms in Alzheimer’s disease (AD), affecting as many as 20–40% of patients. An increasing amount of evidence shows that monoamine-based antidepressant treatments are not completely effective for depression treatment in patients with dementia. Minocycline, a second-generation tetracycline antibiotic, has been gaining research and clinical attention for the treatment of different neuropsychiatric disorders, and more recently depression symptom in humans.
In the present study, we investigated the effects of Aβ1–42 administration alone or in combination with minocycline treatment on depression-like behaviors and anti/pro-inflammatory cytokines such as interleukin(IL)-10, IL-β, and tumor necrosis factor (TNF)-α in the hippocampus of rats.
Our results showed that Aβ1–42 administration increased depression-related behaviors in sucrose preference test, tail suspension test, novelty-suppressed feeding test, and forced swim test. We also found significant increases in IL-1β and TNF-α levels in the hippocampus of Aβ1–42-treated rats. Interestingly, minocycline treatment significantly reversed depression-related behaviors and the levels of hippocampal cytokines in Aβ1–42-treated rats.
These findings support the idea that there is a significant relationship among AD, depression-related symptoms, and pro-inflammatory cytokines in the brain, and suggest that antidepressant-like impacts of minocycline could be due to its anti-inflammatory properties. This drug could be of potential interest for the treatment of depression in patients with Alzheimer’s disease.
KeywordsNeurodegenerative disease Affective disorders Immune system β-Amyloid Antibiotics
Compliance with ethical standards
All experiments were conducted under the recommended conditions of the Guide for the Care and Use of Laboratory Animals of the National Institute of Health (NIH).
Conflict of interest
The authors declare that they have no conflict of interest.
- Banerjee S, Hellier J, Dewey M, Romeo R, Ballard C, Baldwin R, Bentham P, Fox C, Holmes C, Katona C, Knapp M, Lawton C, Lindesay J, Livingston G, McCrae N, Moniz-Cook E, Murray J, Nurock S, Orrell M, O'Brien J, Poppe M, Thomas A, Walwyn R, Wilson K, Burns A (2011) Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet 378:403–411CrossRefPubMedGoogle Scholar
- Benoit M, Berrut G, Doussaint J, Bakchine S, Bonin-Guillaume S, Frémont P, Gallarda T, Krolak-Salmon P, Marquet T, Mékiès C, Sellal F, Schuck S, David R, Robert P (2012) Apathy and depression in mild Alzheimer’s disease: a cross-sectional study using diagnostic criteria. J Alzheimers Dis 31:325–334CrossRefPubMedGoogle Scholar
- Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, Dursun S, Dunn G, Deakin B (2012) Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol 26:1185–1193CrossRefPubMedGoogle Scholar
- Chen L, Li S, Cai J, Wei TJ, Liu LY, Zhao HY, Liu BH, Jing HB, Jin ZR, Liu M, Wan Y, Xing GG (2018) Activation of CRF/CRFR1 signaling in the basolateral nucleus of the amygdala contributes to chronic forced swim-induced depressive-like behaviors in rats. Behav Brain Res 338:134–142CrossRefPubMedGoogle Scholar
- Chermat R, Thierry B, Mico JA et al (1986) Adaptation of the tail suspension test to the rat. Aust J Pharm 17:348–350Google Scholar
- da Silva Dias IC, Carabelli B, Ishii DK, de Morais H, de Carvalho MC, Rizzo de Souza LE, Zanata SM, Brandão ML, Cunha TM, Ferraz AC, Cunha JM, Zanoveli JM (2016) Indoleamine-2, 3-dioxygenase/kynurenine pathway as a potential pharmacological target to treat depression associated with diabetes. Mol Neurobiol 53:6997–7009CrossRefPubMedGoogle Scholar
- de Godoy MA, de Souza AS, Lobo MA et al (2013) Effects of protein restriction during gestation and lactation on cell proliferation in the hippocampus and subventricular zone: functional implications. Protein restriction alters hippocampal/SVZ cell proliferation brain Res 1496:10–27PubMedGoogle Scholar
- Dean OM, Kanchanatawan B, Ashton M, et al (2017) Adjunctive minocycline treatment for major depressive disorder: a proof of concept trial. Aust New Zeal J Psychiatry 0004867417709357Google Scholar
- Emadi-Kouchak H, Mohammadinejad P, Asadollahi-Amin A, Rasoulinejad M, Zeinoddini A, Yalda A, Akhondzadeh S (2016) Therapeutic effects of minocycline on mild-to-moderate depression in HIV patients: a double-blind, placebo-controlled, randomized trial. Int Clin Psychopharmacol 31:20–26CrossRefPubMedGoogle Scholar
- Esmaeili MH, Bahari B, Salari A-A (2018) ATP-sensitive potassium-channel inhibitor glibenclamide attenuates HPA axis hyperactivity, depression- and anxiety-related symptoms in a rat model of Alzheimer’s disease. Brain Res Bull 137:. doi: https://doi.org/10.1016/j.brainresbull.2018.01.001 CrossRefPubMedGoogle Scholar
- Francis-Oliveira J, Ponte B, Barbosa APM, Veríssimo LF, Gomes MV, Pelosi GG, de Britto LRG, Moreira EG (2013) Fluoxetine exposure during pregnancy and lactation: effects on acute stress response and behavior in the novelty-suppressed feeding are age and gender-dependent in rats. Behav Brain Res 252:195–203CrossRefPubMedGoogle Scholar
- Garcez ML, Mina F, Bellettini-Santos T, Carneiro FG, Luz AP, Schiavo GL, Andrighetti MS, Scheid MG, Bolfe RP, Budni J (2017) Minocycline reduces inflammatory parameters in the brain structures and serum and reverses memory impairment caused by the administration of amyloid β (1-42) in mice. Prog Neuro-Psychopharmacology Biol Psychiatry 77:23–31CrossRefGoogle Scholar
- Hansson O, Zetterberg H, Vanmechelen E, Vanderstichele H, Andreasson U, Londos E, Wallin A, Minthon L, Blennow K (2010) Evaluation of plasma Aβ 40 and Aβ 42 as predictors of conversion to Alzheimer’s disease in patients with mild cognitive impairment. Neurobiol Aging 31:357–367CrossRefPubMedGoogle Scholar
- Kosari-Nasab M, Shokouhi G, Ghorbanihaghjo A, Abbasi MM, Salari AA (2018) Anxiolytic- and antidepressant-like effects of Silymarin compared to diazepam and fluoxetine in a mouse model of mild traumatic brain injury. Toxicol Appl Pharmacol 338:338–173. https://doi.org/10.1016/j.taap.2017.11.012 CrossRefGoogle Scholar
- Ledo JH, Azevedo EP, Beckman D, Ribeiro FC, Santos LE, Razolli DS, Kincheski GC, Melo HM, Bellio M, Teixeira AL, Velloso LA, Foguel D, de Felice FG, Ferreira ST (2016) Cross talk between brain innate immunity and serotonin signaling underlies depressive-like behavior induced by Alzheimer’s amyloid-β oligomers in mice. J Neurosci 36:12106–12116CrossRefPubMedGoogle Scholar
- Majidi J, Kosari-Nasab M, Salari A-A (2016) Developmental minocycline treatment reverses the effects of neonatal immune activation on anxiety- and depression-like behaviors, hippocampal inflammation, and HPA axis activity in adult mice. Brain Res Bull 120:1–13. https://doi.org/10.1016/j.brainresbull.2015.10.009 CrossRefPubMedGoogle Scholar
- Miyaoka T, Wake R, Furuya M, Liaury K, Ieda M, Kawakami K, Tsuchie K, Taki M, Ishihara K, Araki T, Horiguchi J (2012) Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog neuro-psychopharmacology Biol Psychiatry 37:222–226CrossRefGoogle Scholar
- Molina-Hernández M, Téllez-Alcántara NP, Pérez-García J, Olivera-Lopez JI, Jaramillo-Jaimes MT (2008) Desipramine or glutamate antagonists synergized the antidepressant-like actions of intra-nucleus accumbens infusions of minocycline in male Wistar rats. Prog Neuro-Psychopharmacology Biol Psychiatry 32:1660–1666CrossRefGoogle Scholar
- Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC, Bruce ML, Caine ED, Cummings JL, Devanand DP, Krishnan KRR, Lyketsos CG, Lyness JM, Rabins PV, Reynolds CF III, Rovner BW, Steffens DC, Tariot PN, Lebowitz BD (2002b) Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry 10:125–128CrossRefPubMedGoogle Scholar
- Paumier KL, Sortwell CE, Madhavan L, Terpstra B, Celano SL, Green JJ, Imus NM, Marckini N, Daley B, Steece-Collier K, Collier TJ (2015) Chronic amitriptyline treatment attenuates nigrostriatal degeneration and significantly alters trophic support in a rat model of parkinsonism. Neuropsychopharmacology 40:874–883CrossRefPubMedGoogle Scholar
- Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates. Academic Press, SixthGoogle Scholar
- Piirainen S, Youssef A, Song C et al (2017) Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer’s disease: the emerging role for microglia? Rev, Neurosci BiobehavGoogle Scholar
- Salari A-A, Fatehi-Gharehlar L, Motayagheni N, Homberg JR (2016) Fluoxetine normalizes the effects of prenatal maternal stress on depression- and anxiety-like behaviors in mouse dams and male offspring. Behav Brain Res 311:354–367. https://doi.org/10.1016/j.bbr.2016.05.062 CrossRefPubMedGoogle Scholar
- Salari A-A, Samadi H, Homberg JR, Kosari-Nasab M (2018) Small litter size impairs spatial memory and increases anxiety-like behavior in a strain-dependent manner in male mice. Sci Rep 8Google Scholar
- Song X, Liu B, Cui L, Zhou B, Liu W, Xu F, Hayashi T, Hattori S, Ushiki-Kaku Y, Tashiro SI, Ikejima T (2017) Silibinin ameliorates anxiety/depression-like behaviors in amyloid β-treated rats by upregulating BDNF/TrkB pathway and attenuating autophagy in hippocampus. Physiol Behav 179:487–493CrossRefPubMedGoogle Scholar
- Souza LC, Jesse CR, Antunes MS, Ruff JR, de Oliveira Espinosa D, Gomes NS, Donato F, Giacomeli R, Boeira SP (2016) Indoleamine-2, 3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid-β 1-42 peptide in mice. Brain Behav Immun 56:363–377CrossRefPubMedGoogle Scholar
- Souza LC, Jesse CR, Del Fabbro L et al (2017) Swimming exercise prevents behavioural disturbances induced by an intracerebroventricular injection of amyloid-β 1-42 peptide through modulation of cytokine/NF-kappaB pathway and indoleamine-2, 3-dioxygenase in mouse brain. Behav Brain Res 331:1–13CrossRefPubMedGoogle Scholar
- Tomás-Camardiel M, Rite I, Herrera AJ, de Pablos RM, Cano J, Machado A, Venero JL (2004) Minocycline reduces the lipopolysaccharide-induced inflammatory reaction, peroxynitrite-mediated nitration of proteins, disruption of the blood–brain barrier, and damage in the nigral dopaminergic system. Neurobiol Dis 16:190–201CrossRefPubMedGoogle Scholar
- Wang H-T, Huang F-L, Hu Z-L, Zhang WJ, Qiao XQ, Huang YQ, Dai RP, Li F, Li CQ (2017) Early-life social isolation-induced depressive-like behavior in rats results in microglial activation and neuronal histone methylation that are mitigated by minocycline. Neurotox Res 31:505–520CrossRefPubMedGoogle Scholar
- Weintraub D, Rosenberg PB, Martin BK, Frangakis C, Mintzer JE, Porsteinsson AP, Schneider LS, Munro CA, Meinert CL, Lyketsos CG, Drye LT, Rabins PV (2010) Sertraline for the treatment of depression in Alzheimer disease: week-24 outcomes. Am J Geriatr Psychiatry 18:332–340CrossRefPubMedPubMedCentralGoogle Scholar
- Zheng L-S, Kaneko N, Sawamoto K (2015) Minocycline treatment ameliorates interferon-alpha-induced neurogenic defects and depression-like behaviors in mice. Front Cell Neurosci 9:Google Scholar