Thrombopoietin exerts a neuroprotective effect by inhibiting the suppression of neuronal proliferation and axonal outgrowth in intrauterine growth restriction rats

• Published in: Experimental neurology 2024-07, Vol.377, p.114781-114781, Article 114781
• Main Authors: Takeshita, Satoru, Kakita, Hiroki, Nakamura, Nami, Mori, Mari, Toriuchi, Kohki, Aoki, Hiromasa, Inoue, Yasumichi, Hayashi, Hidetoshi, Yamada, Yasumasa, Aoyama, Mineyoshi
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Cell Proliferation - drug effects; Cells, Cultured; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Chronic hypoxia; Female; Fetal growth restriction; Fetal Growth Retardation - pathology; Intrauterine growth restriction; Neuronal Outgrowth - drug effects; Neuronal proliferation; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotection; Neuroprotective Agents - pharmacology; Pregnancy; Rats; Rats, Sprague-Dawley; Thrombopoietin
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2024.114781

Chronic hypoxia in utero causes intrauterine growth restriction (IUGR) of the fetus. IUGR infants are known to be at higher risk for neurodevelopmental disorders, but the mechanism is unclear. In this study, we analyzed the structure of the cerebral cortex using IUGR model rats generated through a reduced uterine perfusion pressure operation. IUGR rats exhibited thinner cerebral white matter and enlarged lateral ventricles compared with control rats. Expression of neuron cell markers, Satb2, microtubule-associated protein (MAP)-2, α-tubulin, and nestin was reduced in IUGR rats, indicating that neurons were diminished at various developmental stages in IUGR rats, from neural stem cells to mature neurons. However, there was no increase in apoptosis in IUGR rats. Cells positive for Ki67, a marker of cell proliferation, were reduced in neurons and all glial cells of IUGR rats. In primary neuron cultures, axonal elongation was impaired under hypoxic culture conditions mimicking the intrauterine environment of IUGR infants. Thus, in IUGR rats, chronic hypoxia in utero suppresses the proliferation of neurons and glial cells as well as axonal elongation, resulting in cortical thinning and enlarged lateral ventricles. Thrombopoietin (TPO), a platelet growth factor, inhibited the decrease in neuron number and promoted axon elongation in primary neurons under hypoxic conditions. Intraperitoneal administration of TPO to IUGR rats resulted in increases in the number of NeuN-positive cells and the area coverage of Satb2. In conclusion, suppression of neuronal proliferation and axonal outgrowth in IUGR rats resulted in cortical thinning and enlargement of lateral ventricles. TPO administration might be a novel therapeutic strategy for treating brain dysmaturation in IUGR infants. •IUGR model rats have a thinner cerebral cortex and enlarged lateral ventricles.•Chronic hypoxic ischemia suppresses cell proliferation and axonal outgrowth.•TPO promotes neuronal development and exerts a neuroprotective effect.•TPO could be a therapeutic agent for brain dysmaturation in IUGR infants.