Effects Of Adenosine And Glutamate Metabolized In Astrocytes On Central Nervous System Oxygen Toxicity

Hyperbaric oxygen(HBO) can be applied in many ways, such as submariner escaping,aquanaut work and clinical work. Toxic reaction will occur in organism following theinhalation of the gas with exorbitant partial pressure of oxygen (PO2). If PO2was highenough, the toxic reaction would have taken place very fast. The main clinicalmanifestation of acute oxygen toxicity is the functional disorder of central nervous system(CNS), which is called CNS acute oxygen toxicity.(CNS-OT). One of the most intensiveand representative appearance is convulsion grand mal, named “oxygen convulsion”(OC).Acute oxygen toxicity may induce many troubles, such as drowning while diving,which seriously constraint the utilization of oxygen in underwater military mission,underwater performance for commercial purpose and scientific exploration. The recentinvestigations on the escape of crews from the disabled submarine have pointed out thatpre-breathing hyperbaric oxygen (HBO) before buoyant fast ascent can assure the survivalof crews, and remarkably relieve the condition and sequelae of decompression sickness. Insuch conditions, very high pressure of oxygen will be used in order to balance the pressureequivalent to the depth of submarine accident.Accordingly, to prevent oxygen convulsion effectively is very valuable for safely andfully utilizing HBO in both military and civilian diving operations. By now, it is not veryclear about the mechanism of oxygen convulsion, and the preventive measures are alsopassive, such as limiting the pressure and the time of HBO exposure. Even the profile usedin intermittent HBO exposure, being recognized as the most positive prevention, isempirical, and need much more sufficient scientific evidence to support it. Therefore,intensive investigations on the pathogenesis of oxygen convulsion, especially to determinethe key factors directly relating to its onset, is extremely useful no matter for finding outbetter preventive measures or for optimizing the current intermittent HBO exposureprofile.Recent researches have shown that astrocyte has great effect on formation anddevelopment of epilepsy and the mediation of astrocyte to adenosine and glutamate metabolism plays a key role in generation and propagating of central nervous systemexcitability.Adenosine is a inhibitory gliotransmitter. in synaptic space,ATP released fromadenosine can be degraded to adenosine rapidly by extracellular nucleotidases includingE-NTPDases, E-NPPs, alkaline phosphatase,5’-nucleotidase.Adenosine can inhibit therelease of glutamate when it is combined to its presynaptic A1receptor. It also can blockthe transmission of excitement by activating potassium channelAdenosine is a inhibitory gliotransmitter. in synaptic space, ATP released fromadenosine can be degraded to adenosine rapidly by extracellular nucleotidases includingE-NTPDases, E-NPPs, alkaline phosphatase,5’-nucleotidase.Adenosine can inhibit therelease of glutamate when it is combined to its presynaptic A1receptor. Adenosine canalso activate potassium channel when it is combined to postsynaptic A1receptor, whichmakes postsynaptic neuron hyperpolarized and block the transmission of excitement. Onthe contrary, A2Areceptor can promote the release of excitatory transmitter and accelerateepileptic seizure. The adenosine which is transported into intracellular by Nucleosidetransporter of astrocyte can be phosphorylated to AMP by adenosine kinase(ADK),whichis the only way to clear away the adenosine in synaptic space.Glutamate released from presynaptic membrane can be transported into intracellularby glutamate transporter(GLT-1) which is located on astrocyte membrane,After beingtransformed into glutamine by Glutamine Synthetase(GS),it will be released into synapticspace and transformed into glutamate again.like ADK, GS can only be found in astrocyte.Our study aim to find the possible mechanism how adenosine and glutamate mediatethe CNS-OT by observing the effect of a series of drugs which is related to adenosine andglutamate metabolism on the Latency of CNS-OT.To this end, we carried out thefollowing work:1. We determinated the ATP, ADP, AMP and adenosine of mouse brain after the mousewere exposed to5absolute atmosphere(ATA) hyperbaric oxygen for10min.2. Unlike the other ways of administration of drugs, we used intracerebroventricular injection to avoid the side effect of drugs on other systems which might change the latencyof CNS-OT.3. We intracerebroventricularly injected diffirent dose of adenosine, GLT-1selectiveinhibitor dihydrokainate(DHK), adenosine A1R selective agonist2-chloro-N6-cyclopentyla-denosine(CCPA), adenosine A1R selective antagonist1,3-dipropyl-8-cyclopentylxanthine(DPCPX), adenosine A2AR selective agonist5-(N-cyclopropyl)-carboxamido-adenosine(CPCA), adenosine A2AR selective antagonist5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-c]1,2,4-Triazolo[1,5-c]pyrimidine(SCH58261), ADK inhibitor5’-dITU, GLT-1selective antagonist Ceftriaxoneand observed their effect on the latency of CNS-OT.Main research results:1. Afrer exposure in5ATA HBO, the adenosine of mouse brain increased remarkably,but the ATP, ADP, AMP of mouse brain decreased.2. The latency of CNS-OT can be prolonged when intracerebroventricularly injectingadenosine, adenosine A1R selective agonist(CCPA), A2AR selective antagonist(SCH58261).3. The latency of CNS-OT can be shortened when intracerebroventricularly injectingadenosine A1R selective antagonist(DPCPX), adenosine A2AR selective agonist(CPCA).4. The latency of CNS-OT can be prolonged when intracerebroventricularly injectingADK inhibitor5’-dITU.5. The latency of CNS-OT can be prolonged when intracerebroventricularly injectingGLT-1selective antagonist Ceftriaxone or shortened when intracerebroventricularlyinjecting GLT-1selective inhibitor DHK.