Is age-dependent, ketamine-induced apoptosis in the rat somatosensory cortex influenced by temperature?

Abstract

General anesthetics have long been thought to be relatively safe but recent clinical studies have revealed that exposure of very young children (4 years or less) to agents that act by blocking the N-methyl-D-aspartate receptor (NMDAR) can lead to cognitive deficits as they mature. In rodent and non-human primate studies, blockade of this receptor during the perinatal period leads to a number of molecular, cellular and behavioral pathologies. Despite the overwhelming evidence from such studies, doubt remains as to their clinical relevance. A key issue is whether the primary injury (apoptotic cell death) is specific to receptor blockade or due to non-specific, patho-physiological changes. Principal to this argument is that loss of core body temperature following NMDAR blockade could explain why injury is observed hours later. We therefore examined the neurotoxicity of the general anesthetic ketamine in P7, P14 and P21 rats while monitoring core body temperature. We found that, at P7, ketamine induced the pro-apoptotic enzyme activated caspase-3 in a dose-dependent manner. As expected, injury was greatly diminished by P14 and absent by P21. However, contrary to expectations, we found that core body temperature was not a factor in determining injury. Our data imply that injury is directly related to receptor blockade and is unlikely to be overcome by artificially changing core body temperature.

Ketamine use in current clinical practice

“…Numerous animal studies in rodents indicate that ketamine induces neurodegeneration in the developing brain in a dose-depended manner, and the data also suggest that limiting exposure limits the potential for neurodegeneration. Some postnatal preclinical studies suggested that ketamine-induced injury in the infant rodent brain was a centrally driven event [24,25] . There are very few studies that have examined the potential functional consequences of the neurodegeneration noted in the animal models, except recent evidence suggests that multiple exposures to anesthetics (including ketamine) and surgery before the age of 2 was a significant independent risk factor for the later development of learning disabilities [26] .…”

In vivo and in vitro ketamine exposure exhibits a dose-dependent induction of activity-dependent neuroprotective protein in rat neurons

“…All histological sections were counted using non-biased quantitative investigation stereology as shown by a previous study (Gutierrez et al, 2010). Quantification of AC-3 positive neurons and ADNP-positive neurons were estimated within the somatosensory cortex (layer II/III; SSC II/III ) and fasciola cinereum (FC).…”

“…The stereology procedure was performed using an optical fractionator workflow (StereoInvestigator Ò 10.0; MicroBright Field, Inc., VT, USA) supported by an Olympus BX51 microscope with a 100Â oil immersion objective, an X-Y motorized stage, and a digital camera. As previously described (Gutierrez et al, 2010;Turner et al, 2012), all parameters for counting were set for processed tissue thickness, guard zone and dissector height at 45, 2, and 30 lm, respectively. We used a counting frame size of 75 Â 75 lm 2 and a sampling grid area of 9600 lm 2 adjusted ±2 visiting sites.…”

CNS activation maps in awake rats exposed to thermal stimuli to the dorsum of the hindpaw

“…These have been performed in anesthetized animals with the concomitant confounding effects of anesthesia on CNS processing of pain. Examples include: (i) the use of pentobarbital anesthesia significantly affects nociceptive processing in medial and lateral pain pathways (Wang et al, 2010); (ii) fMRI results may be dependent on the type of anesthetic used; e.g., use of halothane vs. alpha-chloralose anesthetics (Austin et al, 2005); (iii) the concentration or dosing of the anesthetic may modulate the fMRI response in a way that may not correlate with the level of anesthesia and demands high degree of control of anesthesia depth (Austin et al, 2005;Masamoto et al, 2009); (iv) anesthesia (depending upon the drug) may act as a stressor by increasing the levels of cortisol and other stress molecules, such as norepinephrine (Hamstra et al, 1984;Diltoer and Camu, 1988;Kostopanagiotou et al, 2010), and even by producing neurotoxicity (Gutierrez et al, 2010); (v) anesthesia may also induce systemic effects, producing changes in heart rate or blood pressure (Janssen et al, 2004).…”