Ontogenetic Exposure of Rats to Pre- and Post-Natal Manganese Enhances Behavioral Impairments Produced by Perinatal 6-Hydroxydopamine

Abstract

Rats lesioned shortly after birth with 6-hydroxydopamine (6-OHDA; 134 μg icv) represent a near-ideal model of severe Parkinson's disease because of the near-total destruction of nigrostriatal dopaminergic fibers. The element manganese, an essential cofactor for many enzymatic reactions, itself in toxic amount, replicates some clinical features similar to those of Parkinson's disease. The aim of this study was to examine the effect of neonatal manganese exposure on 6-OHDA modeling of Parkinson's disease in rats. Manganese (MnCl(2)·4H(2)O) 10,000 ppm was included in the drinking water of pregnant Wistar rats from the time of conception until the 21st day after delivery, the age when neonatal rats were weaned. Control rats consumed tap water. Other groups of neonatal rat pups, on the 3rd day after birth, were pretreated with desipramine (20 mg/kg ip 1 h) prior to bilateral icv administration of 6-OHDA (30, 60, or 137 μg) or its vehicle saline-ascorbic (0.1%) (control). At 2 months after birth, in rats lesioned with 30, 60, or 134 μg 6-OHDA, endogenous striatal dopamine (DA) content was reduced, respectively, by 66, 92, and 98% (HPLC/ED), while co-exposure of these groups to perinatal manganese did not magnify the DA depletion. However, there was prominent enhancement of DA D(1) agonist (i.e., SKF 38393)-induced oral activity in the group of rats exposed perinatally to manganese and also treated neonatally with the 30 mg/kg dose of 6-OHDA. The 30 mg/kg 6-OHDA group, demonstrating cataleptogenic responses to SCH 23390 (0.5 mg/kg) and haloperidol (0.5 mg/kg ip), developed resistance if co-exposed to perinatal manganese. In the group exposed to manganese and lesioned with the 60 mg/kg dose of 6-OHDA, there was a reduction in D(2) agonist (i.e., quinpirole, 0.1 mg/kg)-induced yawning. The series of findings demonstrate that ontogenetic exposure to manganese results in an enhancement of behavioral toxicity to a moderate dose of 6-OHDA, despite the fact that there is no enhanced depletion of striatal DA depletion by the manganese treatment.

Effect of Pre- and Postnatal Manganese Exposure on Brain Histamine Content in a Rodent Model of Parkinson’s Disease

“…The 60 and 134-lg doses of 6-OHDA were associated with depletions of striatal DA by 92 and 98%, respectively, at 2-months [respectively 909 and 253 vs. 11606 (control) ng/g tissue] (Nowak et al 2011). The same 6-OHDA treatment doses in rats exposed perinatally to manganese resulted in virtually the same magnitude of striatal DA depletion.…”

“…However, in our latest study we demonstrated that ontogenetic exposure to manganese produced an enhancement of behavioral toxicity to a moderate dose of 6-OHDA (60 lg icv) despite the fact that there was no enhanced depletion of striatal DA depletion by manganese treatment (Nowak et al 2011).…”

“…Effects of 6-OHDA and manganese on striatal levels of DOPAC and HVA were similar in magnitude, although there was no enhancement by manganese of the 6-OHDA effects on these DA metabolites. In other brain regions, changes in DA and its metabolites were less prominent although manganese tended to enhance the effects on DA (Nowak et al 2011). …”

Combined Low Calcium and Lack Magnesium Is a Risk Factor for Motor Deficit in Mice

“…25) Recently, it was found that Mn augments the neurotoxic effect of 6-hydroxydopamine, a treatment used to model PD in animals. 26) We do not have data concerning the levels of Mn and Al in the LCa/Mg mice, but these previous results suggest that LCa/Mg in mice can lead to an indirect accumulation of Mn and Al in the brain with subsequent degeneration of DA neurons. We are conducting further experiments in order to elucidate the accumulation of Mn and Al in LCa/Mg mice.…”

Pharmacological evaluation of catalepsy in low calcium and/or magnesium deficient feeding mice

“…Mn neurotoxicity has shown selectivity for DA neurons [22]. Recently, it was demonstrated that Mn augments the neurotoxic effect of 6-hydroxydopamine, a treatment used to model PD in animals [23]. Together, these results suggest that LCa/Mg in mice may lead to an indirect accumulation of Mn and Al in the brain with subsequent degeneration of DA neuron.…”