Perinatal asphyxia results from failure of normal respiratory gas exchange during orrnsoon after labor and it remains an important cause of permanent neurological deficit inrnsurviving infants. The most common features are hypoxia, hypercapnia, and metabolicrnacidosis. The present sf1ldy was undertaken to fUrther characterize the short-term effect ofrnperinatal asphyxia and to investigate a possible preventive role of some Ethiopian medicinalrnplants and hypothermia in rats.rnThe effect of perinatal asphyxia on survival pattern, brain and heart pH, levels ofrnamino acids, monoamines, and glycolytic intermediates was studied using in vivo microdialysisrnand ex vivo biochemistry. Perinatal asphyxia was induced by immersing fef11S containingrnuterus horns, obtained by cesarean section from term pregnant rats, in a water bath at 370Crnfor different periods (0-23 min), according to a non-invasive model that largely mimics thernconditions resulting in asphyxia during human labor (Bjelke et al. , 1991; Andersson et aI.,rn1992; Herrera-Marschitz et al., 1993). Subcutaneous levels of pyruvate, lactate, glutamate,rnand aspartate were monitored with microdialysis 80 ~lin-8 days following delivery. In parallelrnexperiments, pups were sacrificed 40 min after delivery and the brain and heart were removedrnto measure pH In addition, pups were also sacrificed 80 min-8 days after delivery and thernbrain was removed to measure striatal levels of pyruvate, lactate, glutamate, aspartate, andrnmonoamines.rnAt 37Â°C, a decrease in the rate of sU/vival was first observed following asphyxicrnperiod longer than 16 min and no survival was observed after 22 min. pH decreased with thernlength of asphyxia. In control pups (cesarean delivered), brain pH was (7.3Â±0.01;N=6) andrnheart pH was (7.35Â±0.01; N=6). A significant decrease in pH was observed following 10-11rnmin and 5-6 min, in brain and heart respectively. After 80 min of delivery, a significantrnincrease in the levels of all the measured compounds, in subcutaneous and brain tissues, werernobserved follOWing exposure to mild asphyxia. However, the levels started to decline whenrnasphyxia was prolonged With increasing age, the levels of the measured compounds in mildrnâ€¢ asphyxic pups were almost similar as that of the control pups. Nonetheless, the time needed tornrecover depended upon how greatly the compound's metabolism was affected Lactate beingrnthe most severely affected, much time was needed to reduce its level. Thus, changes in systemiCrnpH, glycolytic intermediates, monoamines, and excitatory amino acids metabolism were observed following perinatal asphyxia. In particular, subcutaneous level of lactate preceded:rn(q) a decrease in brain pH, (b) an increase in brain lactate level, (c) a decrease in the rate ofrnsurvival, and probably (d.) brain damage.rnThe possible protective effect of some herbal medicines was evaluated by injecting thernextract subcutaneously or using as a bathing fluid and subjecting the pups to asphyxia atrn370 C. Asphyxia induction at 300C and I50C was also carried out to evaluate the protectiverneffect of hypothermia and to use it for comparison purpose. Survival was prolonged whenrnasphyxia was induced under hypothermic condition. No survival was observed after 50 minrnand 140 min when asphyxia was induced at 300C and I50C respectively. Survival pattern afterrntreatment with plant extracts did not show any significant difference compared to salinerninjected control group. Thus, hypothermia seems the only intervention that can provide goodrnprotective effect amongst the interventions so far evaluated.rnHowever, with improvement in obstetric management, its role has been shown to be limited. Asrnearly as the 1930s, the cause of petlnatal brain damage was intimately tied up with attitudesrntowards the use of sedatives, analgesics, and anesthetics duriug labor and delivery (Eastman,rn1936). It was demonstrated that the excessive use of these agents caused "apnea neonatomm"rnwhich was thought to be the principal cause of cerebral injwy (Sclueiber, 1938) and almost allrnWliters of the time suppOlted this view and equated "asphyxia neonatorum" with "apnearnneonatorwn". Although this view was later shown to be unlikely (Myers, 1977), the tendency tornconsider birth apnea as a causative factor for cerebral injmy dominated-the 1940s-and the 1950s-. -rnHence, articles appeared in the I 940s strongly suggested a causal relationship between petlnatalrnasphyxia and cettain patterns of nemopathogenic changes in the brain. It was stated that thernbrain swelling and necrosis obsetved in newborns who died after cesarean delivety because ofrnpremature detachment of the placenta was due to asphyxia (Clifford, 1941). The injwies at buthrnwere thought to be associated either to trawna to the head or to fetal systemic hypotensionrncaused by asphyxia (Malamud, 1959,1963; Norman, 1969). It was believed that cerebral venousrncongestion causes the haemorrhagic infarction that often affects the brains ofbitth-injwÂ·ed babiesrn(Schwartz, 1961). The congestion was atttibuted to the rapid passage of the fetal head ii-om arnwne of high pressure within the utems to one oflow presswÂ·e outside (Schwaltz, 1961). Therninfarction of the cerebrum associated with birth injwy was caused by fetal circulatOlY failure,rngeneralized venous congestion, and cerebral venous stasis-thrombosis (Towbin, 1970). Thus, arnnwnber of causes have been proposed for petlnatal brain damage of which petlnata1 asphyxia isrnone of the candidates.rnAsphyxia is defined as suffocation with anoxia and increased carbondioxide. It atisesrnfrom impairment of normal respitÂ·atOlY gas exchange with resulting hypoxia/ischemia,rnhypercapnia, and metabolic acidosis. The term perinatal asphyxia is often used to indicate anrnimpainnent of gas exchange during or soon after labor (Nelson and Leviton, 1991; Martin andrnNelson, 1993). The tenn hypoxic-ischemic or postasphyxial encephalopathy is often used torndescribe the illness thought to stem from such impaiIment. In most instances, during thernpeIinatal peIiod, hypoxemia and/or ischemia occm as a result of asphyxia (Hull and Dodd,rn1991). When descIibing oxygen deptivation in hllJDan, the tenn asphyxia is used, because it isrnnot known whether the insult is hypoxic, ischemic, or more probably a combination.rnFmthennore, regarding the fetus, the telms hypoxia and ischemia have been usedrninterchangeably, because, the most common cause of hypoxia in the fetus is hypoperfusion orrnischemia. Hypoxia can also cause ischemia, as it is capable of producing hypotension andrnreduced cardiac output. Thus, in asphyxia, the major additional feature is hypercapnia, whichrnresults in a nllJDber of other metabolic disorders, such as acidosis and physiological effectsrnincluding cerebral vasodilatation (Volpe, 1987). Hypoxia and partial regional ischemiarncommonly occm together, therefore, it appears that the regional distIibution of ischcmia in thernface of hypoxia is a major determinant of the relatively selective nature of peIinatal asphyxialrnbrain injury. Hence, this type of brain injmy is refelTed to as hypoxic-ischemia.rnPelIDatal asphyxia can occm in the human fetus or neonate as an acute total asphyxialrnepisode resulting ii-om cord prolapse that leads to complete cessation of blood flow (Leech andrnAlvord, 1977), and as a prolonged partial asphyxial episode resulting from placental abruptionrnthat may occm during a long and complicated labor (Clifford, 1941). In order to understand thernpatterns of pelIDatal brain damage, two models in monkeys have been developed: acute totalrnasphyxia (Ranck and Windle, 1959) and prolonged partial asphyxia (Brann and Myers, 1975;rnMyers, 1972, 1977). The first model that replicated acute total asphyxia caused a lesionrnaffecting spinal cord, brainstem and thalamus without brain swelling. TIle second model thatrnreplicated prolonged partial asphyxia, however, produced a different pattern of cerebral affecting mainly the COltiCal and subcortical stmctures with brain swelling (Myers, 1972). Thernreason for the different distribntion of the lesions depends upon the redistribution of regionalrncerebral blood flow and the degree of neuronal maturation dwing asphyxia. In most cases, tberntotal pelinatal insnlt in hmnans most likely resnlts from prolonged partial asphyxial episode, andrnsometimes from partia~ combined with terminal acnte asphyxial episode (Scott, 1976; Braun,rn1986). Heuce, fetal partial asphyxia of any cause, independent offetal circnlatOlY collapse andrnhead compression, is believed to be the Priru31Y event that sets in motion a vicious cycle ofbraiurnswelling, leading to stasis of blood flow and, fiually to cerebral necrosis (Br3lill and Myers,rn1975).rnIufOlmatiou about the specific effect of birth asphyxia on the fetus or neouates has beeurnpossible only since the development of new techniques for detennining blood pH and bloodrngases. The introduction of risk scoring and assessment of fetal behavior has finther improved thernidentification of the fetus at risk for a.phyxia (Brallll, 1986; Lowet ai, 1992). Thus, Apgarrn(1953) developed a SCOling system to infer the occurrence of birth asphyxia and to quantifY itsrnsevelity from several indicators, such as: (i) type of breatlling; (ii) healt rate; (iii) color of thernskin; (iv) muscle tone; and (v) response to different sensory stimnli. UnfOltwlately none of thesernindicators is an accurate predictor of outcome, rather they are probably best used to indicate thernneed for active resuscitation (Hnll and Dodd, 1991). Biochemical data such as umbilical pH andrngas levels obtained soon after birtb may be used to validate the judgement tbat thernpathophysiological changes obselved during birth 31'e asphyxial in natme. But these putativernmarkers of asphyxia do not always conelate well with one another.rnBecause of the poor predictive value of the traditional indicators, alternativesand Sarnat, 1976). HIE develops in the first few hours and days of life and is characterized byrnabnonnalities of tone, feeding, level of consciousness, and in the more severe cases, seizures andrnfinally coma with the need for ventilatOlY support. The postasphyxial encephalopathy is gradedrninto mild (no seizure), moderate (seizures) and severe (coma). Those infants with mildrnencephalopathy have a unifonnly good outcome, those with moderate encephalopathy have arn20-30% chance of severe handicap, and the majOlity of infants with severe encephalopathy diern(Hull and Dodd, 1991). Hence, HIE has been found to be a much more accurate predictor ofrnoutcome (Robertson and Finer, 1985), however, the recent identification of a group of infantsrnwith typical encephalopathies (Hull and Dodd, 1991), without previous evidence of asphyxiarncast some doubt on the casual relation between the two phenomena. Thus, there is still nornreliable clinical indicator of birth asphyxia. Nevertheless, with the development of magneticrnresonance spectroscopy, a potential independent indicator of brain asphyxial states has emergedrn(Martin and Nelson, 1993).rnSeveral animal models have been developed to assess the role of asphyxia in mediatingrnbrain damage (see Raju, 1992). In the present thesis, the short-telm effect of perinatal asphyxiarnand its prevention was studied in rat using a novel non-invasive model that largely mimics thernconditions resulting in asphyxia during human labor (Bjelke etaI., 1991; Anderson etal., 1992;rnHerrera-Marschitz etaI., 1993)rnsought. This effort led to the identification of the abnOlmal neurological signs known asrnhypoxic-ischemic encephalopathy (HIE), that was used as an assessment of asphyxia (Samatsinewy