Forsøksdyr: Neurotensin and cooling after birth (copy)

Godkjenningsdato 16.09.2020

Godkjenningsperiode 17.09.2020-17.09.2024

The purpose of this study is to test out if Neurotensin can induce hypothermia in newborn piglets.
Experiments in rodents have demonstrated the potential therapeutic effect of pharmacologically induced hypothermia. Neurotensin is an endogenous neuropeptide with multifunctional biological activities and with high therapeutic potential. It can induce hypothermia and coupled to a peptid-vector it is able to cross the blood-brain barrier(BBB). In rodent experiments intravenous administration of vectorised Neurotensin can reduce brain and body temperature and attenuate brain damage and recent studies performed in rats have shown that a continuous infusion with Neurotensin was able to keep the body temperature within a narrow, controlled range.

Perinatal asphyxia is a major cause of acute mortality and chronic neurologic morbidity. It is important to meet the newborns need for resuscitation in the best possible way and to search for intervention therapies that can improve prognosis and lower mortality.
Hypoxic ischemic encephalopathy(HIE) is a major cause of newborn death and long term complications. Therapeutic hypothermia is the only established neuroprotective treatment. Conventional methods of physical cooling need special equipment and take place in specialized intensive care units. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Pharmacologically induced hypothermia may thereby have a considerable therapeutic potential.
Part one and two of this study was conducted in 2015 and 2017(Project No.7678, 8288 and 13638). We explored the effect of Neurotensine in anaesthetized newborn piglets with or without preceding hypoxia and got promising results. We now want to test out the effect of continuous infusions with Neurotensin starting two hours after end hypoxia and throughout the experiment.
II. The planned experiments are classified as terminal; they will be given a lethal dose of Pentobarbital at the end of the experiment.
During the experiment, the piglet will be cared for with thoughtfulness throughout the experiment. Wrapped in a warm towel a veneflon is placed in a superficial ear vein and the anesthetics are given. Then intubation, mechanical ventilation and placement of arterial and central venous catheters. The piglet stays under full anesthesia and analgesia throughout the experiment.
III. We expect important and relevant results useful for newborn asphyxiated babies as well as all other clinical conditions that may profit from hypothermia.
IV. We will use 48 newborn piglets 12-36hrs of age and in good clinical condition. In case we need to exclude animals, we apply for aditional 12 piglets = total number 60.
V. Replacement: Despite other animal models, there are no other relevant models to study therapeutic interventions after perinatal hypoxia and reoxygenation. Our collaborating group in Marseille has conducted studies in rodents and wanted to proceed to a big animal model like the piglet model due to the anatomical, immunological and brain maturation similarities.
Reduction: We always make calculations concerning probability of significant findings to include as few animals as possible.
Refinement: Our animal model has been used for over three decades and has been continuously improved and refined. Our mortality rate is therefore very low.