ABSTRACT
OBJECTIVES: Caffeine (CAF) and sedative/anesthetic drugs (SADs) are often coadministered to premature infants in the neonatal intensive care unit (NICU). While SAD neurotoxicity in the developing brain is well established, it is not fully clear whether CAF interacts with SADs and whether this interaction is detrimental. Using a mouse model of prematurity, we hypothesized that CAF would increase apoptotic neurotoxicity when coadministered with SADs. METHODS: Postnatal day 3 mice were treated with vehicle or 80 mg/kg CAF prior to challenge with 6 mg/kg midazolam, 40 mg/kg ketamine, or 40 µg/kg fentanyl. Six hours later, pups were sacrificed for activated caspase 3 (AC3) immunohistochemistry, and number of AC3 positive cells per mm3 throughout neocortex, hippocampus, caudate, thalamus, and colliculi was analyzed. RESULTS: CAF caused a statistically significant increase in AC3 positive cells when coadministered with midazolam (p = 0.002), ketamine (p = 0.014), or fentanyl (p < 0.001). Our composite dataset suggests that the addition of CAF to these SADs has a supra-additive effect, causing more neurotoxicity than expected. CONCLUSIONS: CAF may augment the neurotoxic action of SADs indicated for neonatal sedation/anesthesia in the NICU by triggering widespread apoptosis in the developing brains of premature infants.
Subject(s)
Anesthetics/adverse effects , Apoptosis/drug effects , Caffeine/adverse effects , Hypnotics and Sedatives/adverse effects , Neurons/drug effects , Premature Birth/pathology , Anesthetics/administration & dosage , Animals , Animals, Newborn , Caffeine/administration & dosage , Disease Models, Animal , Female , Humans , Hypnotics and Sedatives/administration & dosage , Mice , Mice, Inbred ICR , Neurons/physiology , Neurotoxicity Syndromes/pathology , Pregnancy , Premature Birth/drug therapy , Premature Birth/psychology , Random AllocationABSTRACT
One of the more fascinating recent discoveries in neuroscience is the widespread influence of hormones on brain regions and functions underlying pathological behaviors. A story is unfolding that points to critical roles played by hypothalamic - pituitary - gonadal (HPG) and hypothalamic - pituitary - adrenal (HPA) axes on a startling array of mental disorders, from depression to dementia. The influence of peptides and steroids does not end with hormones released from the two axes, however. It is now clear that the brain has adapted, "highjacked" is more descriptive, HPG and HPA hormones for uses unrelated to their original functions in reproduction and responses to stress. Findings of neuromodulatory effects of HPA and HPG hormones on monoamine, GABA, glutamate and opioid pathways and of hormone receptors and enzymes involved in hormone synthesis, particularly of steroids, in the hippocampus, amygdala and other subcortical brain regions provide the brain with multiple evolutionary means to adapt to new functions. The complexity of the metabolic cascade for the steroids also leaves open mechanisms by which endogenous errors and exogenous chemicals could be involved in the etiology of psychopathologies. The planned review will examine the recent literature for evidence of steroidal and peptidergic influences on basic biological functions and on mood disorders, anxiety and PTSD, schizophrenia, substance abuse and dementia. Emphasis will be placed on animal models, although findings with patient populations will be prominently included. Special attention will be paid to novel pathways by which the precursors and metabolites of sex steroids can influence psychopathologies. We also will speculate on promising treatments with hormone modulators that may be useful in mollifying the symptomology of the mental disorders.
