Naringin and Sertraline Ameliorate Doxorubicin-Induced Behavioral Deficits Through Modulation of Serotonin Level and Mitochondrial Complexes Protection Pathway in Rat Hippocampus

Abstract

The present study was designed to investigate the neuroprotective effect of naringin (NR) alone as well as its combination with sertraline (SRT) against doxorubicin (DOX)-induced neurobehavioral and neurochemical anomalies. DOX (15 mg/kg; i.p.) administration caused behavioral alterations, oxidative stress, neuroinflammation, mitochondrial dysfunction and monoamines alteration in male Wistar rats. NR (50 and 100 mg/kg; i.p.) and SRT (5 mg/kg; i.p.) treatment significantly attenuated DOX-induced anxiety and depressive-like behavior as evident from elevated plus maze (EPM) and modified forced swimming test (mFST), respectively. NR treatment significantly attenuated DOX-induced raised plasma corticosterone (CORT), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) levels in the hippocampus (HC). Furthermore, we found that combination of NR and SRT regimen ameliorated DOX-induced behavioral anomalies through modulation of the 5-HT level and mitochondrial complexes protection pathway along with alleviation of oxidative stress in the HC region. Therefore, NR treatment alone or in combination with SRT could be beneficial against DOX-induced neurotoxicity.

Aerobic exercise, but not metformin, prevents reduction of muscular performance by AMPk activation in mice on doxorubicin chemotherapy

“…DOX caused increase in corticosterone, as observed in previous studies (de Lima et al, ; Kwatra et al, ; Preziosi, Vacca, Ragazzoni, del Carmine, & Navarra, ). Increased corticosterone levels induce increase in both catabolic pathways (ubiquitin–proteasome and autophagy) in skeletal muscle.…”

“…Other authors have shown similar results, where DOX treatment increased the expression of autophagic proteins and that exercise can negatively regulate them (Campbell & Quadrilatero, 2016;Smuder, Kavazis, Min, & Powers, 2011). DOX-mediated autophagy is caused by increased mitochondrial uncoupling with the elevation of reactive oxygen species (ROS) production, and the exercise is able to increase antioxidant defense, leading to the reduction in ROS generation (Schwalm et al, 2015;Smuder et al, 2011) DOX caused increase in corticosterone, as observed in previous studies Kwatra et al, 2016;Preziosi, Vacca, Ragazzoni, del Carmine, & Navarra, 1989). Increased corticosterone levels induce increase in both catabolic pathways (ubiquitin-proteasome and autophagy) in skeletal muscle.…”

Dopamine and dopamine receptor D1 associated with decreased social interaction

“…Neurons in the hippocampus can overdrive DA and 5-HT to distort the emotional change [22,23]. Thus, we detected the levels of these neurotransmitters in the hippocampus by using HPLC.…”

Mechanisms of Neurotoxic Symptoms as a Result of Breast Cancer and Its Treatment: Considerations on the Contribution of Stress, Inflammation, and Cellular Bioenergetics

“…Doxorubicin treatment has been associated with impairments in hippocampal mitochondrial enzyme complexes I and II and with redox activity in rats [49]. Cisplatin treatment was shown to decrease neuronal mitochondrial capacity on the level of spare respiratory capacity [97, 98], which translates to reduced capacity to increase energy production when demand increases.…”

“…Verbal memory performance in survivors was predicted by an interaction between hippocampal volume and TNF-α. Most of the breast cancer survivors in this study (>80%) had received a chemotherapeutic cocktail including doxorubicin, which was shown in an animal model to increase TNF-α (and IL-1β) in the hippocampus [49]. Thus, the association between circulating TNF-α and hippocampal volume found in the clinical study possibly reflects associations between central TNF-α and hippocampal volume, leading to cognitive symptoms.…”