Vesna Jevtovic-Todorovic

General Anesthetics and Neurotoxicity: How Much Do We Know?

Over a decade ago, alarming findings were reported that exposure of the very young and very old animals to clinically used general anesthetics could be detrimental to their brains. The evidence presented suggested that the exposure to commonly used gaseous and intravenous general anesthetics induces the biochemical and morphologic changes in the immature and aging neurons ultimately resulting in their demise. More alarming was the demonstration of significant cognitive and behavioral impairments noted long after the initial anesthesia exposure. This article provides an overview of anesthesia-induced developmental neurotoxicity and commentary on the effects of general anesthesia on the aging brain.

The role of T‐type calcium channels in the subiculum: to burst or not to burst?

Pharmacological, molecular and genetic data indicate a prominent role of low‐voltage‐activated T‐type calcium channels (T‐channels) in the firing activity of both pyramidal and inhibitory interneurons in the subiculum. Pharmacological inhibition of T‐channels switched burst firing with lower depolarizing stimuli to regular spiking, and fully abolished hyperpolarization‐induced burst firing. Our molecular studies showed that CaV3.1 is the most abundantly expressed isoform of T‐channels in the rat subiculum. Consistent with this finding, both regular‐spiking and burst firing patterns were profoundly depressed in the mouse with global deletion of CaV3.1 isoform of T‐channels. Selective inhibition of T‐channels and global deletion of CaV3.1 channels completely suppressed development of long‐term potentiation (LTP) in the CA1–subiculum, but not in the CA3–CA1 pathway.

A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain

Background: More than 4 million children are exposed annually to sedatives and general anaesthetics (GAs) in the USA alone. Recent data suggest that common GAs can be detrimental to brain development causing neurodegeneration and long‐term cognitive impairments. Challenged by a recent US Food and Drug Administration (FDA) warning about potentially neurotoxic effects of GAs in children, there is an urgent need to develop safer GAs. Methods: Postnatal Day 7 (P7) rat pups of both sexes were exposed to six (repeated every 2 h) injections of equipotent hypnotic doses of ketamine or the neuroactive steroid (3&bgr;,5&bgr;,17&bgr;)‐3‐hydroxyandrostane‐17‐carbonitrile (3&bgr;‐OH) for 12 h. Loss of righting reflex was used to assess hypnotic properties and therapeutic index; quantitative caspase‐3 immunohistochemistry was used to assess developmental neuroapoptosis; patch‐clamp recordings in acute brain slices were used to assess the effects of 3&bgr;‐OH on neuronal excitability and synaptic transmission. Cognitive abilities of rats exposed to ketamine, 3&bgr;‐OH, or vehicle at P7 were assessed in young adulthood using the radial arm maze. Results: The neuroactive steroid 3&bgr;‐OH has a therapeutic index similar to ketamine, a commonly used clinical GA. We report that 3&bgr;‐OH is safe and, unlike ketamine, does not cause neuroapoptosis or impair cognitive development when administered to P7 rat pups. Interestingly, 3&bgr;‐OH blocks T‐type calcium channels and presynaptically dampens synaptic transmission at hypnotically‐relevant brain concentrations, but it lacks a direct effect on &ggr;‐aminobutyric acid A or glutamate‐gated ion channels. Conclusions: The neurosteroid 3&bgr;‐OH is a relatively safe hypnotic that warrants further consideration for paediatric anaesthesia.

Early Exposure to Ketamine Impairs Axonal Pruning in Developing Mouse Hippocampus

Mounting evidence suggests that prolonged exposure to general anesthesia (GA) during brain synaptogenesis damages the immature neurons and results in long-term neurocognitive impairments. Importantly, synaptogenesis relies on timely axon pruning to select axons that participate in active neural circuit formation. This process is in part dependent on proper homeostasis of neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF). We set out to examine how GA may modulate axon maintenance and pruning and focused on the role of BDNF. We exposed post-natal day (PND)7 mice to ketamine using a well-established dosing regimen known to induce significant developmental neurotoxicity. We performed morphometric analyses of the infrapyramidal bundle (IPB) since IPB is known to undergo intense developmental modeling and as such is commonly used as a well-established model of in vivo pruning in rodents. When IPB remodeling was followed from PND10 until PND65, we noted a delay in axonal pruning in ketamine-treated animals when compared to controls; this impairment coincided with ketamine-induced downregulation in BDNF protein expression and maturation suggesting two conclusions: a surge in BDNF protein expression “signals” intense IPB pruning in control animals and ketamine-induced downregulation of BDNF synthesis and maturation could contribute to impaired IPB pruning. We conclude that the combined effects on BDNF homeostasis and impaired axon pruning may in part explain ketamine-induced impairment of neuronal circuitry formation.

Selective inhibition of CaV3.2 channels reverses hyperexcitability of peripheral nociceptors and alleviates postsurgical pain

Preventing the stabilization of a Ca2+ channel at the surface of sensory neurons attenuates postsurgical pain. Preventing postsurgical pain Opiate abuse has necessitated finding alternative therapeutic targets to alleviate postsurgical pain. The Ca2+ channel CaV3.2 has been implicated in inflammatory and neuropathic pain. Joksimovic et al. now show that postsurgical pain also triggers CaV3.2 channel activity by increasing its stability at the surface of pain-sensing neurons. In rodents, pharmacologically inhibiting CaV3.2 or preventing the deubiquitinating enzyme USP5 from stabilizing the channel reversed postoperative hypersensitivity to mechanical and heat stimuli, pain syndromes that are also typical in patients after surgery. Targeting CaV3.2 or the ability of USP5 to bind to the channel may provide a strategy for relieving postsurgical pain that lacks the addiction potential of opiates. Pain-sensing sensory neurons of the dorsal root ganglion (DRG) can become sensitized or hyperexcitable in response to surgically induced peripheral tissue injury. We investigated the potential role and molecular mechanisms of nociceptive ion channel dysregulation in acute pain conditions such as those resulting from skin and soft tissue incision. We used selective pharmacology, electrophysiology, and mouse genetics to link increased current densities arising from the CaV3.2 isoform of T-type calcium channels (T-channels) to nociceptive sensitization using a clinically relevant rodent model of skin and deep tissue incision. Furthermore, knockdown of the CaV3.2-targeting deubiquitinating enzyme USP5 or disruption of USP5 binding to CaV3.2 channels in peripheral nociceptors resulted in a robust antihyperalgesic effect in vivo and substantial T-current reduction in vitro. Our study provides mechanistic insight into the role of plasticity in CaV3.2 channel activity after surgical incision and identifies potential targets for perioperative pain that may greatly decrease the need for narcotics and potential for drug abuse.

Using animal models to evaluate the functional consequences of anesthesia during early neurodevelopment

Fifteen years ago Olney and colleagues began using animal models to evaluate the effects of anesthetic and sedative agents (ASAs) on neurodevelopment. The results from ongoing studies indicate that, under certain conditions, exposure to these drugs during development induces an acute elevated apoptotic neurodegenerative response in the brain and long-term functional impairments. These animal models have played a significant role in bringing attention to the possible adverse effects of exposing the developing brain to ASAs when few concerns had been raised previously in the medical community. The apoptotic degenerative response resulting from neonatal exposure to ASAs has been replicated in many studies in both rodents and non-human primates, suggesting that a similar effect may occur in humans. In both rodents and non-human primates, significantly increased levels of apoptotic degeneration are often associated with functional impairments later in life. However, behavioral deficits following developmental ASA exposure have not been consistently reported even when significantly elevated levels of apoptotic degeneration have been documented in animal models. In the present work, we review this literature and propose a rodent model for assessing potential functional deficits following neonatal ASA exposure with special reference to experimental design and procedural issues. Our intent is to improve test sensitivity and replicability for detecting subtle behavioral effects, and thus enhance the translational significance of ASA models.