A bout analysis reveals age-related methylmercury neurotoxicity and nimodipine neuroprotection

Abstract

Age-related deficits in motor and cognitive functioning may be driven by perturbations in calcium (Ca2+) homeostasis in nerve terminals, mechanisms that are also thought to mediate the neurotoxicity of methylmercury (MeHg). Calcium-channel blockers (CCBs) protect against MeHg toxicity in adult mice, but little is known about their efficacy in other age groups. Two age groups of BALB/c mice were exposed to 0 or 1.2 mg/kg/day MeHg and 0 or 20 mg/kg/day of the CCB nimodipine for approximately 8.5 months. Adults began exposure on postnatal day (PND) 72 and the retired breeders on PND 296. High-rate operant behavior was maintained under a percentile schedule, which helped to decouple response rate from reinforcer rate. Responding was analyzed using a log-survivor bout analysis approach that partitioned behavior into high-rate bouts separated by pauses. MeHg-induced mortality did not depend on age but nimodipine neuroprotection was age-dependent, with poorer protection occurring in older mice. Within-bout response rate (a marker of sensorimotor function) was more sensitive to MeHg toxicity than bout-initiation rate (a marker of motivation). Within-bout rate declined almost 2 months prior to overt signs of toxicity for the MeHg-only retired breeders but not adults, suggesting greater delay to toxicity in younger animals. Motor-based decrements also appeared in relatively healthy adult MeHg + NIM animals. Aging appeared to alter the processes underlying Ca2+ homeostasis thereby diminishing protection by nimodipine, even in mice that have not reached senescence. The study of MeHg exposure presents an experimental model by which to study potential mechanisms of aging.

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

“…To ensure that the doses of nimodipine used both in vivo and in vitro in our study were clinically relevant, we followed the recommendations in published studies (6, 13, 18, 50, 51). All doses described in the quoted literature were able to attenuate cognitive deficits in models of neurodegenerative diseases and to trigger endogenous hormone responses, so it is likely that sufficient levels of the drug were achieved in the CNS (13,50,52). Furthermore, many studies on subarachnoidal hemorrhage have shown that the dosages used in animal studies are able to induce comparable effects in patients (51, 52).…”

“…Proapoptotic effects of DMSO or ethanol alone were also excluded by performing corresponding vehicle-control experiments. To ensure that our in vitro dose of nimodipine was clinically relevant, we studied the literature closely and tested doses that already had been used in several CNS disease models (13,18,50,51). The dose used for cell culture had been shown to induce equivalent effects in patients (e.g., reduced stress-mediated effects after brain surgery and decreased excitotoxicity) (51).…”

Nimodipine attenuates dibutyl phthalate‐induced learning and memory impairment in kun ming mice: An in vivo study based on bioinformatics analysis

“…In addition, Ming et al 21 showed that nimodipine (Nim), a dihydropyridine Ca 2+ antagonist, could activate neuroprotective signaling events to protect the brain. Despite the mounting evidence showing that Nim has a direct effect on neurons, has neuropharmacological and psychopharmacological efficacy, and can protect and promote memory and cognitive recovery., 21,22 there are few reports regarding the effects of Nim on learning and memory impairment caused by exposure to PAEs.…”