FRANK J. MILNE STATE-OF-THE-ART LECTURE


cephalopathy (HIE), Perinatal Asphyxia Syndrome, and other names have been used. The question for me was why do 80% of foals with this severe hypoxia recover within 2 to 7 days, with no residual neuro- logical deficits? In any other mammal, hypoxia that is sufficient to cause clinical signs of hypother- mia, reduced gut motility, compromise of the renal system, hypoventilation, seizures, weakness, disori- entation, failure to recognize the maternal source of milk, etc., causes long-term adverse outcomes. This is not the case with the maladjusted foal. We have found in the dummy foal and other sick foals, a persistence of the sedative neurosteroids, which play a role in keeping foals from galloping in utero. This can, and does, cause the clinical signs seen in dummy foals and opens a huge avenue of potential for prompt reversal of symptoms. Learn- ing about these neurosteroids is important. We be- lieve that the pressure of the birth canal during stage 2 labor, which is supposed to last 20 minutes, is an important signal that tells the foal to quit producing the sedative neurosteroids and wake up. We are in the early stages of treating the dummy foal by recreating the birth process via a squeeze system to mimic 20 minutes of birth canal pressure. The preliminary results have been dramatic.


Neurosteroids: Background


Certain steroidal compounds, predominantly 5-re- duced pregnanes, can cross the blood brain barrier and have neuromodulatory effects as neuroactive steroids (neurosteroids).144 These pregnane me- tabolites are primarily synthesized within the cen- tral nervous system (CNS) from cholesterol, via progesterone, by 5-reductase action but can also be synthesized in other tissues and readily cross the blood brain barrier.145 These neuroactive steroids modulate gamma-aminobutyric acid (GABA), gluta- mate and opioid neurotransmission affecting brain development and functioning.146 Steroids exert or- ganizational and activational actions during brain development and modulate neurotransmission ei- ther by directly interacting with neurotransmitter receptors or by genetic mechanisms. Pregnenolone sulphate and dehydroepiandrosterone (DHEA) sul- phate are excitatory, being allosteric antagonists of


GABAA receptors and agonists of N-methyl-D-as- partate (NMDA) receptors, whereas pregnenolone, allopregnanolone, and androsterone are allosteric


agonists of GABAA receptors and are neuroinhibi- tory.146 The final neurophysiological outcome may, therefore, depend on the relative ratios of excitatory and inhibitory steroids.


The Transition From Fetus to Neonate


Unequivocal changes in mammalian fetal steroid hormones are a prerequisite for the transition from the quiescent intrauterine fetal state to active extra- uterine life where suckling and following the dam within a few hours of birth is required. The uterus plays a key role in providing the chemical and phys-


122 2014  Vol. 60  AAEP PROCEEDINGS


ical factors that together help to keep the fetus con- tinuously asleep. This is thought to be achieved through the combined neuroinhibitory actions of a powerful EEG suppressor and sleep inducing agent (adenosine), two neurosteroidal anesthetics (allo- pregnanolone, pregnanolone), and a potent sleep- inducing hormone (prostaglandin D2), acting together with a putative peptide inhibitor and other factors produced by the placenta, further supported by the warmth and cushioned tactile stimulation of the uterine environment.147 Injections of pro- gesterone or its metabolites into the ovine fetal circulation in late gestation reduce fetal electroen- cephalograph, electrocorticograph, and electrooculo- graph activity, breathing movements and behavioral arousal, while inhibition of placental pro- gesterone enhance these parameters.148–151 The loss of placentally-derived precursors at birth


and the switch to adrenal or other derived precur- sors causes a dramatic decline in pregnane concen- trations shortly after birth in healthy neonates.152 Studies of healthy neonatal foals have shown high concentrations of pregnanes at birth that decrease rapidly, to essentially zero, over the first 48 hours of life.153,154 Reduction of these CNS depressant pregnanes is accompanied by increased alertness and arousal.


Infusion of Pregnanes to Healthy Neonates: An Inducible Model of Neonatal Maladjustment Syndrome?


Infusion of two healthy neonatal foals with the preg- nane allopregnanolone induced obtundation, lack of affinity for the mare and decreased response to ex- ternal stimuli,155 similar to clinical signs observed in neonatal maladjustment syndrome (NMS) foals. Similarly, infusion of 5-reduced pregnanes into ro- dents leads to anesthesia or marked behavioral ef- fects156 suggesting that these pregnanes cross the blood-brain barrier and exert neuromodulatory ef- fects. The effects observed following allopregnano- lone infusion were short-lasting and associated with measurable concentrations of pregnanes, which peaked in conjunction with maximum neurobehav- ioral effects, and EEG abnormalities such as slow wave sleep while standing (Estell et al, unpublished data, 2013). Allopregnanolone also caused brady- cardia and subjectively decreased gastrointestinal borborygmi due to either general sedative effects of the steroid or potentially increased vagal tone (Es- tell et al, unpublished data, 2013). A range of neurobehavioral abnormalities are ob-


served in NMS including obtundation, seizures, and hyperesthesia. Whilst the infused steroid allopreg- nanolone has a dampening effect in the CNS, others within the large spectrum of neurosteroids, includ- ing metabolites of allopregnanolone, have excitatory effects that may be associated with seizures and hyperesthesia.157


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