Widespread Neonatal Brain Damage following Calcium Channel Blockade

Abstract

An abundance of evidence exists that shows calcium channel blockade promotes injury in cultured neurons. However, few studies have addressed the in vivo toxicity of such agents. We now show that the L-type calcium channel antagonist nimodipine promotes widespread and robust injury throughout the neonatal rat brain, in an age-dependent manner. Using both isolated neuronal as well as brain slice approaches, we address mechanisms behind such injury. These expanded studies show a consistent pattern of injury using a variety of agents that lower intracellular calcium. Collectively, these observations indicate that postnatal brain development represents a transitional period for still developing neurons, from being highly sensitive to reductions in intracellular calcium to being less vulnerable to such changes. These observations directly relate to current therapeutic strategies targeting neonatal brain injury.

Effects of Disrupting Calcium Homeostasis on Neuronal Maturation: Early Inhibition and Later Recovery

“…Thus, although this agent can induce robust apoptosis in neonatal animals (Ikonomidou et al 1999;Turner et al 2002;Turner et al 2007b), the data we now present suggest more subtle effects may also occur, which include inhibition of the developmental program of MK801-sensitive neurons. A critical question that remains is whether MK801 promotes cell death independent of inhibition of neuronal maturation or does such inhibition actually initiate cell death?…”

“…However, even within the same study, both low and high neuronal calcium levels have been shown to induce growth cone collapse (Mattson and Kater 1987;Kater et al 1988), suggesting that growth cone motility, as well as neurite growth and arborization, may require optimal levels of calcium, deviations above or below which result in negative outcomes. Similarly, neuronal survival may depend on maintaining a "calcium set point," first proposed by Eugene Johnson (Johnson et al 1992) and later used by our group to explain neuronal death observed in P7 rats exposed to MK801 (Turner et al 2002;Turner et al 2007a;Turner et al 2007b). Indeed, more recently we have shown that MK801-induced injury in P7 rats is observed in cells that lack the CaBPs calbindin-D28K, calretinin, or parvalbumin (Lema Tomé et al 2006).…”

“…P7 rat pups treated with MK801 display robust apoptosis in multiple brain regions (Ikonomidou et al 1999;Lema Tomé et al 2006;Turner et al 2007b), suggesting significant rewiring of the CNS should be expected. However, not only do these animals survive but they also appear to be, in a general sense, behaviorally normal, suggesting that essential CNS circuits remain intact or are plastic enough to recover from MK801-induced injury.…”

“…Maintaining calcium homeostasis during the postnatal period may be critical to still-developing neurons as blockade of calcium entry through the N-methyl-D-aspartate receptor (NMDAR; a calcium permeant ion channel), or voltage-operated calcium channels, can induce caspase-3-dependent apoptosis in postnatal day 7 (P7) rats (Turner et al 2007b). Injury was found in neurons that did not express the calcium-binding proteins (CaBPs) calbindin-D28K, calretinin, or parvalbumin (Lema Tomé et al 2006Tomé et al , 2007, suggesting that still-developing neurons less able to regulate calcium homeostasis may be vulnerable to agents that alter intracellular calcium.…”

Effects of Lamotrigine Alone and in Combination with MK-801, Phenobarbital, or Phenytoin on Cell Death in the Neonatal Rat Brain

“…The trend toward enhancing phenytoin effects with 30 mg/kg LTG also supports this possibility. It is tempting to speculate that the protective action of LTG could be mediated by interfering with phenytoin-induced impairment of calcium entry (Lacinova, 2005) (low intracellular calcium levels have been shown to contribute to neonatal neuronal apoptosis; Lema Tomé et al, 2006a;Turner et al, 2007). At higher doses of LTG, the inhibition of sodium channels may exacerbate the similar action of phenytoin, further suppressing neuronal activity and stimulating cell death.…”