Novel neurosteroid anesthetics and developmental synaptogenesis

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Summary Exposure of young children to general anesthetics (GAs) is common in medicine; however, emerging data suggest that this practice may be detrimental to brain development, resulting in long-term cognitive impairments. Since currently used GAs known to be neurotoxic to the immature brain exert their action by modulating two main receptor systems – GABA and NMDA – we suggest the general hypothesis that novel anesthetics with different cellular targets might be safe and promising alternative. One such alternative is a family of neuroactive steroids with blocking action on low-voltage-activated T-type calcium channels known to be important for neuronal excitability and synaptic transmission. Our long-term goal is to develop novel GAs that will provide the same reliability and efficacy as currently available ones but without devastating long-term consequences. We are off to a promising start since T-channel-blocking neuroactive steroids are not only powerful analgesics but also effective hypnotics. Most importantly, compared with other injectable (and inhaled) anesthetics, they appear to be much less harmful to the developing brain based on our preliminary pathomorphological and functional findings. Our rationale is that the design of safer anesthetics for use in children should be guided by the presently available understanding of the mechanisms responsible for developmental neurotoxicity of currently used GAs. To that end, we will use ex vivo and in vivo rat models of GA-induced developmental neurotoxicity to address the specific hypothesis that novel neuroactive steroids with blocking action on T-channels, unlike clinically-used GAs, are effective and safe anesthetics for use during critical stages of brain development. Aim #1: Characterizes anesthetic properties of novel neuroactive steroid analogs that are T-channel blockers (e.g. 3-OH and ECN) and GABAA agonists (e.g. ACN, CDNC24 and alphaxalone) and compares their anesthesia profile in rats and mice with commonly used injectable anesthetic, propofol. Preliminary data suggest that 3-OH is safe and effective and, compared with ketamine, it exhibits higher efficacy and potency when administered to rat pups (at post-natal day 7). Aim #2: Examines neurotoxic potential of neuroactive steroid analogs vis-à-vis propofol (known to cause significant developmental neurotoxicity) by focusing on morphological and functional features of GA-induced impairments of synaptogenesis (e.g. acute apoptotic cell death, delayed impairment in synapse formation/maintenance, integrity of mitochondria, neuronal survival and impairment in synaptic transmission). Aim #3: Scrutinizes long- term functional outcomes of an early exposure to novel neuroactive steroid analogs with particular focus on neuronal communication in hippocampal ex vivo slice preparation and in vivo assessment of cognitive development. Our preliminary findings suggest a lack of cognitive impairment after an early exposure to 3- OH. Aim #4: Takes rodent studies to the next level by examining the anesthetic properties and safety of a chosen neuroactive steroid (as determined in Aims 1-3) in infant non-human primates.