4Chemobrain in rats: Behavioral, morphological, oxidative and inflammatory effects of doxorubicin administration

Author(s)

Cardoso, Carolina Vieira ^[1] ; de Barros, Marcelo Paes ^[2] ; Lacerda Bachi, Andre Luis ^{[3, 4]} ; Bernardi, Maria Martha ^[1] ; Kirsten, Thiago Berti ^[1] ; Monteiro Martins, Maria de Fatima ^[5] ; Dell'Armelina Rocha, Paulo Ricardo ^[1] ; Rodrigues, Paula da Silva ^[1] ; Bondan, Eduardo Fernandes ^[1]

Affiliation

^[1] Univ Paulista, Grad Program Environm & Expt Pathol, Rua Doutor Bacelar 1212, 4th Floor, BR-04026002 Sao Paulo, SP - Brazil

^[2] Univ Cruzeiro Sul, Inst Phys Act & Sports Sci ICAFE, Rua Galvao Bueno 868, Bldg B, 13th Floor, BR-01506000 Sao Paulo, SP - Brazil

^[3] Brazilian Inst Teaching & Res Pulm & Exercise Imm, Rua Pedro Ernesto 240, BR-12245520 Sao Jose Dos Campos, SP - Brazil

^[4] Univ Fed Sao Paulo, Dept Otorhinolaryngol, Rua Pedro de Toledo 947, BR-04039002 Sao Paulo, SP - Brazil

^[5] Univ Cruzeiro Sul, Sch Vet Med, Ave Tenente Laudelino Ferreira do Amaral 700, BR-08060000 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Behavioural Brain Research; v. 378, JAN 27 2020.
• Web of Science Citations: 0

Abstract

Doxorubicin (DOX) is known to cause cognitive impairments in patients submitted to long-term chemotherapy (deficits also known as chemobrain). The present study investigated whether DOX administration could affect behavior and brain morphology, as well as oxidative and inflammatory status in rats. Male Wistar rats were injected with DOX (2.5 mg/kg/week, 4 weeks, i.p.) or saline. Behavioral analyses were performed. Brains were collected and analyzed by hematoxylin-eosin and luxol fast blue staining techniques and by immunohistochemistry (for glial fibrillary acidic protein expression in astrocytes; GFAP). Serum and brain levels of TNF-alpha, IL-1 beta, IL-6, IL-8, IL-10 and CXCL-1 were determined. Oxidative parameters, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), nitric oxide (NO center dot), brain iron and ferritin levels, as well as reduced and oxidized glutathione (GSH and GSSG, respectively) and thiobarbituric acid reactive substances (TBARS) were also assessed in brain. DOX-injected rats presented cognitive/memory impairments, increased GFAP expression, increased levels of TBARS, NO and GR, but decreased GSSG and ferritin levels in brain homogenate. In addition, increased serum and brain levels of IL-6, IL-8 and CXCL1 were noted in the DOX group, although IL-10 decreased. As DOX has a poor penetration across the blood-brain barrier (BBB), it is proposed that this drug elicits a systemic proinflammatory response with increase of proinflammatory cytokines which cross the BBB and can be involved in the induction of oxidative molecules and proinflammatory cytokines that altogether induce astrogliosis all over the brain. These events may be responsable for chemotherapy-induced cognitive/memory deficits. (AU)

• FAPESP's process: 17/06032-2 - Biochemical, physiological and transcriptomic strategies to study the relationship between carotenoids, oxidative stress and Citrus fruit quality
• Grantee: Marcelo Paes de Barros
• Support Opportunities: Scholarships abroad - Research