4-((3-(1-6-dihyro-6-oxo-9h-purin-9-yl)-1-oxopropyl)amino)benzoic-acid and Disease-Models--Animal

Periventricular leukomalacia (PVL) is the dominant form of brain injury in premature infants and no specific treatment is currently available. Neotrofin, a neurotrophin agonist, has been shown to provide neuroprotection in several in vivo and in vitro studies. The aim of this study was to investigate the neuroprotective effect of neotrofin treatment after endotoxin induced PVL in a rat model. Wistar rat pups were divided into four groups as: (1) control, (2) lipopolysaccharide (LPS)-administered group, (3) LPS-administered and prenatal maternal neotrofin-treated group and (4) LPS-administered and postnatal neotrofin-treated group. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) was administered consecutively at the 18th and 19th embryonic days to establish endotoxin-induced PVL model. In the prenatal treatment group dams received an i.p. injection of neotrofin (60 mg/kg) following after the second LPS dose; and in the postnatal treatment group rat pups received i.p. injection of neotrofin (60 mg/kg) at birth. At P7, apoptosis and hypomyelination in periventricular white matter were evaluated by immunohistochemical assessments. The prenatal maternal neotrofin treatment significantly reduced the number of apoptotic cell death and greatly prevented LPS-stimulated loss of hypomyelinization. However, neotrofin treatment in the postnatal period was not as effective as intrauterine treatment. Given our results, neotrofin may be useful in reducing brain injury and possessing clinical relevance for the treatment of white matter injury in newborns.

Topics: Aminobenzoates; Animals; Animals, Newborn; Apoptosis; Brain; Caspase 3; Disease Models, Animal; Female; Humans; Hypoxanthines; Immunohistochemistry; In Situ Nick-End Labeling; Infant, Newborn; Leukomalacia, Periventricular; Lipopolysaccharides; Maternal-Fetal Exchange; Myelin Basic Protein; Neurons; Neuroprotective Agents; Pregnancy; Rats; Rats, Wistar

Hypoxia-ischemia is a major cause of perinatal brain injury in the newborn. Neotrofin, a neurotrophin agonist, has been shown to provide neuroprotection in several in vivo and in vitro studies. The aim of this study is to investigate the neuroprotective and ameliorating effects of neotrofin treatment after hypoxic-ischemic-injury-induced neuronal cell death, apoptosis in a neonatal hypoxic-ischemic brain injury rat model. Twenty-one seven-day-old Wistar rat pups were used in this study. The groups were: (1) a neotrofin-treated hypoxic-ischemic-group, (2) a saline-treated hypoxic-ischemic-group, and (3) a sham-operated group. Rat pups were subjected to left carotid artery occlusion followed by 2.5h of hypoxic exposure. After the hypoxic exposure, group one received an intra-peritoneal injection of neotrofin at a dose of 60mg/kg. Forty-eight hours after hypoxia, the animals were killed for histopathological evaluation to detect apoptosis and density of neurons. We found that neotrofin attenuates hypoxia-ischemia induced with neuronal density of the hippocampus, the prefrontal and the parietal cortex, and decreased apoptotic cell index in the same regions. Given our results, neotrofin may be useful in reducing brain injury; it possesses clinical relevance for the treatment of hypoxic-ischemic encephalopathy in the newborn.

Topics: Aminobenzoates; Animals; Animals, Newborn; Apoptosis; Disease Models, Animal; Female; Fetal Hypoxia; Hypoxanthines; Hypoxia-Ischemia, Brain; Male; Nerve Degeneration; Neuroprotective Agents; Rats; Rats, Wistar