Neuroprotective interaction produced by xenon and dexmedetomidine on in vitro and in vivo neuronal injury models.
Xenon, an NMDA receptor antagonist and dexmedetomidine (Dex), an alpha(2)-adrenoceptor agonist, both exhibit neuroprotective effects. We investigated the nature of their interaction. In vitro: a primary co-culture of neuronal and glial cells derived from neonatal mice was exposed to oxygen and glucose deprivation (OGD) and the resulting neuronal injury was assessed by the release of lactate dehydrogenase (LDH). In vivo: Postnatal rats aged 7 days underwent right common carotid artery ligation followed by 90 min of hypoxia. The area of infarction was assessed at four days post-injury by morphological criteria. Long-term neurological function was evaluated at 30 days post-injury by testing co-ordination on rotarod. Both xenon and Dex concentration-dependently reduced LDH release with IC50 values of 42% atm (95% CI: 35-52) and 0.10 microM (95% CI: 0.08-0.16), respectively. Isobolographic analysis showed that combined effect of xenon and Dex in vitro was additive. In vivo, a combination of xenon and Dex, at doses that are individually not neuroprotective, produced significant neuroprotective effect as measured by reduction in area of infarction. The long-term neurological function data corroborated these morphological data. Our study demonstrates that the combination of xenon and Dex offers neuroprotection additively in vitro and synergistically in vivo.
Rajakumaraswamy
Nishanthan
N
Departments of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom.
Ma
Daqing
D
Hossain
Mahmuda
M
Sanders
Robert D
RD
Franks
Nicholas P
NP
Maze
Mervyn
M
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy / Q000473:pathology; D017536:Carotid Artery, Common / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects; D020927:Dexmedetomidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005947:Glucose / Q000172:deficiency; D002534:Hypoxia, Brain / Q000188:drug therapy / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008026:Ligation; D051379:Mice; D008807:Mice, Inbred BALB C; D009457:Neuroglia / Q000187:drug effects* / Q000473:pathology*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D018696:Neuroprotective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D014978:Xenon / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D018685:Anesthetics, Inhalation; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D014978:Xenon; D020927:Dexmedetomidine; D007770:L-Lactate Dehydrogenase; D005947:Glucose