Drug‐induced Apoptotic Neurodegeneration in the Developing Brain

Abstract

Physiological cell death (PCD), a process by which redundant or unsuccessful neurons are deleted by apoptosis (cell suicide) from the developing central nervous system, has been recognized as a natural phenomenon for many years. Whether environmental factors can interact with PCD mechanisms to increase the number of neurons undergoing PCD, thereby converting this natural phenomenon into a pathological process, is an interesting question for which new answers are just now becoming available. In a series of recent studies we have shown that 2 major classes of drugs (those that block NMDA glutamate receptors and those that promote GABAA receptor activation), when administered to immature rodents during the period of synaptogenesis, trigger widespread apoptotic neurodegeneration throughout the developing brain. In addition, we have found that ethanol, which has both NMDA antagonist and GABAmimetic properties, triggers a robust pattern of apoptotic neurodegeneration, thereby deleting large numbers of neurons from many different regions of the developing brain. These findings provide a more likely explanation than has heretofore been available for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). The period of synaptogenesis, also known as the brain growth spurt period, occurs in different species at different times relative to birth. In rats and mice it is a postnatal event, but in humans it extends from the sixth month of gestation to several years after birth. Thus, there is a period in pre‐ and postnatal human development, lasting for several years, during which immature CNS neurons are prone to commit suicide if exposed to intoxicating concentrations of drugs with NMDA antagonist or GABAmimetic properties. These findings are important, not only because of their relevance to the FAS, but because there are many agents in the human environment, other than ethanol, that have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers (ethanol, phencyclidine [angel dust], ketamine [Special K], nitrous oxide [laughing gas], barbiturates, benzodiazepines), and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

“…54 All lead to apoptosis in a variety of cells. [55][56][57][58] Death induced in C8 and A9 cells after exposure to EtOH (2.5%), CHX (25 mg/ml), or CPT (20 mM) for 18 h was determined by trypan blue (TB) exclusion assay. Owing to their sensitivity to low serum (1% FBS), untreated control C8 cells manifested of the order of 15% cell death ( Figure 1A).…”

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

“…Activation of NMDARs is essential for long-term potentiation and spatial learning and memory (Malenka and Bear, 2004), and NMDAR blockade results in impaired synaptic plasticity manifested as adverse effects on learning and memory (Sakimura et al, 1995;Shimizu et al, 2000). It has been shown that higher doses of ketamine can induce neuroapoptosis in rodents (Maxwell et al, 2006;Olney et al, 2002a;Wang et al, 2005) and primates (Haberny et al, 2002;Slikker et al, 2007b;Wang et al, 2006) during early development. In agreement, we have previously reported that ketamine induces motor neuron toxicity in zebrafish embryos .…”

“…Reports also show that exposure of the developing brain to a clinically relevant cocktail of anesthetics that has both NMDA antagonist and GABA mimetic properties results in an extensive pattern of neuroapoptosis, and subsequent cognitive deficits (Olney et al, 2002b). Several reports have illustrated that ketamine can induce neuronal apoptosis when administered in high doses and/or for prolonged durations during susceptible periods of development in rodents (Maxwell et al, 2006;Olney et al, 2002a;Wang et al, 2005) and primates (Haberny et al, 2002;Slikker et al, 2007a;Wang et al, 2006) and these effects can manifest on later disruptions in cognitive function (Paule et al, 2011). To minimize risks to children exposed to anesthesia, it is paramount to understand how anesthetic drugs affect the developing nervous system and whether those effects can be ameliorated or prevented.…”

Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95

“…Blockade of the NMDAR induces widespread apoptosis and worsening of ongoing neurodegeneration in the developing and adult central nervous system. [44][45][46] Environmental enrichment, which stimulates synaptic activity, inhibits spontaneous apoptosis in the hippocampus and is neuroprotective. 47 Regarding the consequences of the decrease in function of extrasynaptic NMDARs, coupled to cell-death pathways, 14 a protective role might be suggested.…”