DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine

Abstract

Amantadine (AMA) is an uncompetitive antagonist of the N-methyl-d-aspartate receptor, with clinical application, acting on treatment of influenza A virus and Parkinson's disease. It has been proposed that AMA can indirectly modulate dopaminergic transmission. In high doses, the central nervous system is its primary site of toxicity. To examine deleterious effects on CNS induced by AMA, this study evaluated possible neurobehavioral alterations induced by AMA such as stereotyped behavior, the effects on locomotion and memory and its possible genotoxic/mutagenic activities. Adult male CF-1 mice were treated with a systemic injection of AMA (15, 30 or 60 mg kg(-1) ) 20 min before behavioral tasks on open field and inhibitory avoidance. Higher AMA doses increased the latency to step-down inhibitory avoidance test in the training session in the inhibitory avoidance task. At 60 mg kg(-1) AMA induced impairing effects on locomotion and exploration and hence impaired habituation to a novel environment. Stereotyped behavior after each administration in a 3-day trial was observed, suggesting effects on dopaminergic system. Amantadine was not able to induce chromosomal mutagenesis or toxicity on bone marrow, as evaluated by the micronucleus assay. At the lowest dose tested, AMA did not induce DNA damage and it was unable to impair memory, locomotion, exploration or motivation in mice. However, higher AMA doses increased DNA damage in brain tissue, produced locomotor disturbances severe enough to preclude testing for learning and memory effects, and induced stereotypy, suggesting neurotoxicity.

Effects of Memantine, a Non-Competitive N-Methyl-d-Aspartate Receptor Antagonist, on Genomic Stability

“…Drugs acting in the central nervous system and in endogenous neurotransmitters can induce DNA damage in brain tissue [1–3]. Glutamate is a neurotransmitter capable of inducing excitotoxicity in neurodegenerative diseases like Parkinson and Alzheimer, mediated by release of calcium, which can initiate a cascade of intracellular signals that result in oxidative stress [4,5].…”

“…There are few studies on the effects of aminoadamantane drugs on genomic stability. A recent study has shown genotoxic effects of amantadine assessed by comet assay in blood and brain tissues of mice [3]. In this study, we evaluated the possible genotoxic/antigenotoxic and mutagenic effects of memantine.…”

Brain DNA damage and behavioral changes after repeated intermittent acute ethanol withdrawal by young rats

“…Additionally, it is known that the exposure to stress promotes neuronal changes, including apoptosis, morphological changes, and increased risk of brain damage (Joëls et al 2007). On the other hand, Kaefer et al (2010) observed that DNA damage affected locomotion, thus impairing the animal's behavioral tests, and demonstrating that neurotoxicity can be associated directly with neurobehavioral changes. Therefore, a causality relationship between ethanol withdrawal with anxiety and oxidative DNA damage is impossible to establish at this time, and future studies to elucidate this matter need to be planned.…”

A Systems Approach to Study Immuno- and Neuro-Modulatory Properties of Antiviral Agents

“…Amantadine and rimantadine were not recommended for the treatment of IAV infections in 2009, because 100% of the seasonal, as well as the 2009 influenza pandemic strains, carried resistance to the drugs [ 12 ]. Amantadine side effects were also associated with the impairment of central nervous system activity [ 13 ].…”