Unexpected Improvements of Spatial Learning and Memory Abilities in Chronic Rotenone Intoxicated Mice

Abstract

The liposoluble insecticide rotenone is commonly used as a mitochondrial complex I inhibitor to replicate Parkinson's disease (PD) pathological features. However, there was no assessment of the spatial learning and memory abilities in chronic rotenone-induced PD models. In the present study, by rotarod test and Thioflavine T staining, we first noted the impairment of motor coordination in rotenone-treated group for 3 months, as well as alpha-synuclein inclusions in the nigral dopaminergic neurons in C57BL/6 mice with intragastrical delivery of rotenone (5 mg/Kg) for 3 months rather than 1 month. We then evaluated spatial learning and memory abilities by Morris water maze task in this model. The results showed escape latency reduced in rotenone-intoxicated mice for 3 months, indicating an improvement of learning ability. However, it was delayed slightly but not significantly in rotenone-intoxicated mice for 1 month. Similarly, we demonstrated that spatial memory ability was enhanced in 3-month-treatment group, but impaired in 1-month-treatment group. There were no proliferating cell nuclear antigen and doublecortin positive cells in the hippocampus by double immunofluorescent staining, indicating the absence of hippocampal neurogenesis in rotenone-intoxicated mice. These results suggest that spatial learning and memory abilities are disturbed in chronic rotenone-intoxicated PD model.

An update on the rotenone models of Parkinson's disease: Their ability to reproduce the features of clinical disease and model gene–environment interactions

“…Cognitive decline 472 Cognition was shown to be altered in rotenone-treated rats as 473 transfer latency in the elevated plus-maze learning task was 474 prolonged in comparison to controls; the detected high levels of 475 acetylcholinesterase activity was subsequently proposed to be a 476 possible contributor to this cognitive decline (Kaur et al, 2011).477 Memory impairment has also been reported in rotenone-treated 478 rats as they failed to detect the novel object with equal time spent 479 with the familiar and novel object in the object recognition test 480 (DosSantos et al, 2013). A recent study similarly reported a defect 481 in spatial memory in mice treated with rotenone at 5 mg/kg 482 intragastrically 5 days a week for 1 month(Jia et al, 2014). 483 Remarkably when this dosing paradigm was extended to 3 months 484 the rotenone mice had improved spatial learning and memory(Jia 485 et al, 2014), highlighting the need for further investigation to 486 understand the pathophysiology behind these findings.487 2.3.5.…”

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

“…For mice, the concentration range used for intragastric rotenone administration is 0.25 mg/kg (min) to 50 mg/kg (max), and the concentration used is dependent on the exposure duration. For the exposure duration of 14-28 days, higher concentrations (30-50 mg/kg) were used (Chiu et al, 2015;Inden et al, 2007;Takeuchi et al, 2009), whereas 5 mg/kg was used for longer exposure up to 3 months (Jia et al, 2014;Pan-Montojo et al, 2010).…”

“…Other frequently-reported key intermediate events include decrease in glutathione (Hosamani & Muralidhara, 2009;Sanchez-Reus et al, 2007;Saravanan et al, 2005;Swarnkar et al, 2010;Xiong et al, 2009b) or dopamine levels (Abdin & Hamouda, 2008;Alam & Schmidt, 2002;He et al, 2003;Hosamani & Muralidhara, 2009;Inden et al, 2007;Ling et al, 2004b;Milusheva et al, 2005;Monti et al, 2010;Saravanan et al, 2005;Sindhu et al, 2005;Xiong et al, 2009b), altered dopamine metabolism (Antkiewicz-Michaluk et al, 2003;Antkiewicz-Michaluk et al, 2004;Ling et al, 2004b;Monti et al, 2010;Santiago et al, 2010), increased oxidative stress such as increased ROS/peroxynitrite production Hosamani & Muralidhara, 2009;Panov et al, 2005;Saravanan et al, 2005) and lipid peroxidation (Bashkatova et al, 2004;Betarbet et al, 2006;Chiu et al, 2015;Hosamani & Muralidhara, 2009;Inden et al, 2007;Jia et al, 2014;Monti et al, 2010;PanMontojo et al, 2010;Sanchez-Reus et al, 2007;Sherer et al, 2003b;Swarnkar et al, 2010;Wu et al, 2015;Xiong et al, 2009b), altered neurite formation (Esteve-Rudd et al, 2011;Fan et al, 2011;…”

“…Two well-reported key downstream events in vivo are dopaminergic neurodegeneration and locomotor deficits (Abdin & Hamouda, 2008;Alam & Schmidt, 2002;Bashkatova et al, 2004;Coulom & Birman, 2004;Fan et al, 2011;Gao et al, 2012;Hosamani & Muralidhara, 2009;Inden et al, 2007;Jia et al, 2014;Pan-Montojo et al, 2010;Santiago et al, 2010;Sindhu et al, 2005;Swarnkar et al, 2010;Takeuchi et al, 2009;Wu et al, 2015;Xiong et al, 2009b). Dopaminergic neurodegeneration was most observed in the substantia nigra (Fan et al, 2011;Gao et al, 2012;Inden et al, 2007;Ling et al, 2004b;Monti et al, 2010;Pan-Montojo et al, 2010;Phinney et al, 2006;Saravanan et al, 2005;Sherer et al, 2003a;Sherer et al, 2003b;Takeuchi et al, 2009;Wu et al, 2015;Xiong et al, 2009b) followed by the striatum (Alam & Schmidt, 2002;Betarbet et al, 2006;Betarbet et al, 2000;Milusheva et al, 2005;Monti et al, 2010;Pan-Montojo et al, 2010;Saravanan et al, 2005;Sherer et al, 2003a;Sherer et al, 2003b;Wu et al, 2015;Xiong et al, 2009b).…”

“…Other regions of dopaminergic neurodegeneration include retina (Esteve-Rudd et al, 2011) and the brains of adult fruit flies (Coulom & Birman, 2004). Overall neurodegeneration including nondopaminergic neurons (Fan et al, 2011;Ferrante et al, 1997;Santiago et al, 2010;Sindhu et al, 2005) as well as other behavioural features such as depression (Gao et al, 2012;Santiago et al, 2010) and altered spatial learning/memory (Jia et al, 2014) have been reported. However, undesired effects such as mortality in rats as well as in fruit flies and peripheral abnormalities (e.g.…”