[P1.25]: Modulation of CD38 and Cx43 in astrocytes as new neuroprotective strategy at perinatal hypoxic‐ischemic brain damage

Abstract

We have studied CD38, Cx43 expression in rat brain cells after perinatal hypoxic-ischemic injury. We found regulation of CD38 by modulators of metabolism of endogenous retinoic acid or by exogenous retinoic acid and Cx43 by glycirretinoic acid. Possibility to use the data for development of pharmacological method of neuroprotection is discussed.To elicit hypoxic-ischemic perinatal brain injury, 7-day-old perinatal (P7) rats (n = 40) were subjected to right carotid artery ligation followed 1 h of 8% oxygen exposure (Rice J., 1981). Control animals (n = 20) were sham-operated. Biological material (front and occipital brain areas) was taken away in 4, 8, 72 hours, 10 days after the operation for preparing frozen slices. Expression of CD38, Cx43, GFAP, MAP2, modulation of Cx43 activity in astrocytes by 5 M glycirretinoic acid (GRA), modulation of CD38 in vivo by retinoic acid (RA) (20 mg/kg), fluorimetric measurement of CD38 were done.CD38 expression after hypoxic-ischemic brain damage raises 8 h after brain injury following by reducing in P17 to control meanings. The amount of Cx43 + and GFAP + cells increases in acute period of hypoxia, what attracted Cx43 + -astrocytes enhancement in damage area. On postischemic 10th day 80% of Cx43 + -cells and 42% of GFAP + cells are CD38-immunopositive, but amount of MAP2 + cells reduces as well as number of MAP2 + CD38 + neurons. Cx43 inhibitor GRA reduces ADP-ribosyl cyclase activity. RA decreases CD38 expression in astrocytes.Acute period of perinatal hypoxic/ischemic brain injury attends by reactive astrogliosis, change of CD38 and Cx43 expression in astrocytes is marker of neuroglial interactions disturbances after perinatal CNS injury, modulation of which by RA regulators and GRA make a base for new therapeutic neuroprotective strategy at perinatal period.Perinatal hypoxia-ischemia (HI) brain damage remains the major cause of acute mortality in newborns and can cause deep cognitive and motor deficiencies in infants and children. However, there is not an efficient mean to avoid the consequences of this severe impairment. As preconditioning (PC) strengthens endogenous cellular defences, triggering preconditioning is a promising strategy to develop new and safe therapies. Low doses of carbon monoxide (CO) prevent cell death in primary cultures of astrocytes and neurons. Moreover, this endogenous molecule can induce a PC cellular state, which involves reactive oxygen species (ROS) as signalling intermediaries. Thus, the objective of the present work was to apply CO as an agent able to decrease tissue injury via PC-induction and cell death prevention in a rat model of perinatal brain HI. Rat pups were exposed to 250 ppm for 1 h (37 • C) at day 4, 5 and 6 after birth and hypoxia-ischemia was induced at P7, according to adaptations in the Vannucci model (left carotid artery ligation and 75 min of 8% O 2 ). The brains were collected 24 h and 1 week after HI for cell death and tissue protection assessment by histological analysis. Whereas apoptotic bodies were abundant in the hipp...