Behavioral Effects Induced by Mitochondria-Targeted Antioxidant SkQ1 in Wistar and Senescence-Accelerated OXYS Rats

Abstract

Abstract. Mitochondrial dysfunction is involved in aging and in neurodegenerative diseases and, therefore, pharmacological agents that alleviate mitochondrial dysfunction are expected to have neuroprotective effects. Promising in this respect is mitochondrial-targeted antioxidant plastoquinonyl-decyl-triphenylphosphonium (SkQ1). We investigated the effects of SkQ1 (250 nmol SkQ1/kg × day with food) on behavior in the elevated plus-maze (EPM) and open field (OF) and on spatial memory in a Morris water maze (MWM) in middle-aged (12 mo) Wistar and senescence-accelerated OXYS rats. Given that changes in the behavior of OXYS rats may be associated with visual impairment, the condition of the retina and the lens was evaluated by ophthalmoscopy. 14-month-old as well as 3-month-old OXYS rats had considerably reduced activities in OF, increased anxiety in EPM, and manifested impaired learning abilities in the MWM in comparison with Wistar rats. SkQ1-treated rats of both strains displayed significantly higher locomotor and exploratory activity in the OF and less anxiety in the EPM compared to age-matched controls. SkQ1 significantly improved visual ability of the rats reducing the severity of the developed signs of retinopathy and cataract but had no impact on OXYS rat's spatial memory in the MWM. SkQ1-treated Wistar rats exhibited slower learning in the MWM task comparison to the control group. Thus, SkQ1 had beneficial effects on locomotor and exploratory functions of the rat brain. Nevertheless, SkQ1 did not alter learning performance in the MWM in OXYS rats and slightly reduced it in the Wistar strain, which may be associated with differences in redox homeostasis.

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

“…The mitochondria-targeted antioxidant SkQ1 is the most effective antioxidant in reducing the severity of the manifestations of accelerated brain aging; for example, it slows down pathological accumulation of AβPP and Aβ and attenuates hyperphosphorylation of the tau protein in OXYS rats. 40,41 Based on all of our results discussed above, we can conclude that mitochondrial dysfunction and the imbalance in immune response are key for the development of AD-like pathology in OXYS rats. We believe that further experiments with the OXYS rat strain will yield new insights into the complex mechanisms underlying AD and may lead to new therapeutic strategies to combat this disease.…”

“…40,41,43 At the age of 3 mo, OXYS rats exhibit significantly reduced locomotor and exploratory activities in the open field test and increased anxiety in the elevated plus maze test. These impairments progressively increased with age in OXYS rats, compared with Wistar rats.…”

“…49 We have shown that young (age 3 mo) and middle-aged (age 12-16 mo) Wistar rats display the same level of spatial learning, whereas learning and memory deficits in OXYS rats became progressively worse between ages 3 and 16 mo, pointing to gradual deterioration of cognitive function. [40][41][42][43] In contrast, OXYS rats demonstrate learning and reference memory deficits in the 8-arm radial maze already at 3 mo of age (data in preparation).…”

Beneficial effects of melatonin in a rat model of sporadic Alzheimer’s disease

“…OXYS rats are characterized by progressive age-related aggregation of amyloid-b and hyperphosphorylation of the tau protein as well as mitochondrial dysfunction, loss of synapses, neuronal death, and ultimately cognitive decline (Stefanova et al 2010(Stefanova et al , 2011(Stefanova et al , 2014a. We demonstrated previously that the signs of accelerated aging of the brain in OXYS rats develop simultaneously with changes in the metabolism of the neurotransmitter serotonin in the brain regions that are essential for learning and memory (Shcheglova et al 2002).…”

“…The OXYS rat strain was derived from the Wistar rat strain at the Institute of Cytology and Genetics as described earlier (Stefanova et al 2010) and was registered in the Rat Genome Database (http://rgd. mcw.edu/).…”