Dietary nimodipine delays the onset of methylmercury neurotoxicity in mice

Abstract

Adult-onset methylmercury (MeHg) exposure is thought to result primarily in sensory and motor deficits but effects on learning are poorly understood. One mechanism by which chronic MeHg may exert its neurotoxicity is via sustained disruption of intracellular calcium homeostasis, with a consequent increase of intracellular Ca(2+) ions in vulnerable neurons. A biochemically heterogeneous group of compounds, calcium channel blockers, have been shown in vitro to attenuate MeHg's toxicity. To evaluate the role of calcium antagonism in MeHg toxicity in vivo, adult BALB/c mice were exposed chronically to 0 or 15 ppm of Hg (as MeHg) via drinking water and to nimodipine, a dihydropryidine, L-type Ca(2+) channel blocker with action in the CNS. Nimodipine was administered orally in diets (0, 20, or 200 ppm, producing approximately 0, 2, or 20 mg/kg/day of nimodipine). An incremental repeated acquisition (IRA) of response chains procedure was used to detect MeHg-induced deficits in learning or motoric function and to evaluate possible neuroprotection by nimodipine. MeHg impaired performance on the IRA task, and this was partially or completely blocked by dietary nimodipine, depending on dose. Measures of learning co-varied with measures of motoric function as indicated by overall response rate. Nimodipine delayed or prevented the behavioral toxicity of MeHg exposure as evidenced by IRA performance; effects on learning seemed secondary to response rate decreases.

Figure 1

Top row is PQ score from the performance condition and the bottom row is from the learning condition of the IRA procedure. The left column contains data from the 0- ppm MeHg exposure group, for each of the three nimodipine condition (0, 20 and 200 ppm nimodipine). The right column contains data from the 15 ppm MeHg exposure group for each nimodipine condition. Data points represent the mean for each group as a function of MeHg exposure day. The curves represent a LOESS smoothing algorithm.

Figure 2

Maximum chain length (MCL) reached across experimental days for the exposure groups, structured similarly as figure 1.

Figure 3

Response rate across experimental days for each exposure group, structured similarly as figure 1.

Figure 4

PQ (top), response rate (middle) and reinforcer rate (bottom) data from the last 5 sessions of performance (left) and learning (right) for the control (open circle) and 15 ppm MeHg (filled circle) groups as a function of nimodipine dose (x-axis).

Figure 5

Relationship between progress quotient (PQ) score and maximum chain length (MCL) (top left), PQ and response rate (responses/min) (top right) and reinforcer rate (reinforcers/min) and response rate (bottom right) during performance (filled circles) and learning (open circles) sessions from the last five days of the experiment. (Note: −0.1 has been applied to performance MCL and +0.1 has been applied to learning MCL).

Figure 6

MeHg brain concentration from the 0ppm MeHg 0 ppm nimodipine group (left-most position) and each chronic MeHg (15 ppm MeHg) exposure group across three nimodipine groups (0, 20 and 200 ppm nimodipine). Brain tissue was analyzed at the end on the experiment. “*” indicates p < .0001.