Clinical anesthesia causes permanent damage to the fetal guinea pig brain.

Exposure of the immature brain to general anesthesia is common. The safety of this practice has recently been challenged in view of evidence that general anesthetics can damage developing mammalian neurons. Initial reports on immature rats raised criticism regarding the possibly unique vulnerability of this species, short duration of their brain development and a lack of close monitoring of nutritional and cardiopulmonary homeostasis during anesthesia. Therefore, we studied the neurotoxic effects of anesthesia in guinea pigs, whose brain development is longer and is mostly a prenatal phenomenon, so that anesthesia-induced neurotoxicity studies of the fetal brain can be performed by anesthetizing pregnant female pigs. Because of their large size, these animals made invasive monitoring of maternal and, indirectly, fetal well-being technically feasible. Despite adequate maintenance of maternal homeostasis, a single short maternal exposure to isoflurane, whether alone or with nitrous oxide and/or midazolam at the peak of fetal synaptogenesis, induced severe neuroapoptosis in the fetal guinea pig brain. As detected early in post-natal life, this resulted in the loss of many neurons from vulnerable brain regions, demonstrating that anesthesia-induced neuroapoptosis can cause permanent brain damage.

General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain.

Brain-derived neurotrophic factor (BDNF) is important in supporting neuronal development. BDNF imbalance due to excessive neuronal inhibition can result in the apoptotic degeneration of developing neurons. Since general anesthetics cause profound depression of neuronal activity and are known to induce widespread degeneration in the developing brain, we studied their potential to activate BDNF-mediated developmental neuroapoptosis. When P7 rats (at the peak of brain development) were exposed to a commonly-used and highly pro-apoptotic anesthesia protocol (midazolam, isoflurane, nitrous oxide) for a period of 2, 4 or 6 h, we found that anesthesia modulates the key steps in BDNF-activated apoptotic cascade in two of the most vulnerable brain regions--cerebral cortex and thalamus in time-dependent fashion by activating both Trk-dependent (in thalamus) and Trk-independent p75NTR dependent (in cerebral cortex) neurotrophic pathways. beta-estradiol, a sex hormone that upregulates the protein levels of the activated Akt, protects against anesthesia-induced neuroapoptosis.

Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain.

General anesthetics cause widespread apoptotic neurodegeneration in many regions of the developing rat brain. The activation of mitochondria-dependent apoptotic pathway is important in the early stages of anesthesia-induced developmental neuroapoptosis. To investigate potential means of protecting against this type of damage, we studied melatonin, a sleep-promoting agent and antioxidant known to inhibit apoptotic-type neuronal damage by improving mitochondrial homeostasis and stabilizing the inner mitochondrial membrane. When 7-day-old rats (the peak of synaptogenesis) were exposed to a commonly used and highly pro-apoptotic anesthesia cocktail (midazolam, isoflurane, nitrous oxide) in combination with the escalating doses of melatonin (from 1 to 20 mg/kg, s.c.), the severity of anesthesia-induced damage was reduced in a dose-dependent manner in two most vulnerable brain regions--the cerebral cortex and anterior thalamus. Melatonin-induced neuroprotection was mediated, at least in part, via the inhibition of mitochondria-dependent apoptotic pathway since melatonin caused an up-regulation of the anti-apoptotic protein, bcl-X(L), reduction in anesthesia-induced cytochrome c release into the cytoplasm and a decrease in anesthesia-induced activation of caspase-3, an important step in the activation of DNAses and the formation of the apoptotic bodies.

The anesthetics nitrous oxide and ketamine are more neurotoxic to old than to young rat brain.

Nitrous oxide (N2O) and ketamine are common general anesthetics and antagonists of N-methyl-D-aspartate (NMDA) glutamate receptors. In clinically relevant concentrations, they induce a psychotomimetic reaction in humans and pathomorphological changes in the rat brain. We have previously shown that ketamine and N2O in combination cause the neurotoxic reaction in young adult rat brain that is apparently synergistic. Ketamine and N2O are occasionally used in geriatric anesthesia since they do not suppress cardiorespiratory function and thus are beneficial for frail elderly patients. However, in view of the evidence that N2O and ketamine have potentially serious neurotoxic effects, and that they potentiate one another's neurotoxicity, their neurotoxic potential in the aging brain needs to be evaluated. In this study we compared the neurotoxicity of ketamine and N2O, alone or in combination, in aging (18- and 24-month-old) rats and in young adult (6-month-old) rats and found that the aging brain is substantially more sensitive than the young adult brain to the neurotoxic reaction induced by either ketamine alone or the ketamine + N2O combination, but equally sensitive to the neurotoxicity induced by N2O alone.