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Pierre Gressens‘ Neurodevelopment and Neuroprotection ’

Abstract :

Neuroprotection of the perinatal brain is a health care priority and a major challenge for the 21st century both in terms of suffering and economy.
Injury to the perinatal brain is a leading cause of death and disability in children. The major brain lesions associated with cerebral palsy and cognitive impairment are periventricular white matter damage (PWMD) mostly occurring in preterm infants and cortico-subcortical lesions mostly observed in term infants.

Epidemiological and experimental data have allowed deciphering the pathophysiology of perinatal brain damage and, therefore, the identification of potential targets for neuroprotection. Several prenatal, perinatal and postnatal factors have been implicated. Although some of the potentially noxious factors are present in utero and were shown to be sufficient to cause permanent injury to the developing brain prior to neonatal life, several groups have hypothesized that some of these factors act as predisposing or sensitizing factors (“pro-damage conditions”), increasing the susceptibility to injury when a second unfavourable event occurs (multiple hit hypothesis).

Promising neuroprotective strategies are emerging and clinical trials are currently testing the efficacy of some of these approaches, raising the hope that efficient treatments will be eventually available in the future to protect the newborn brain.

Despite these major advances in the field of perinatal neuroprotection, several important questions are still the focus of debate and need to be addressed. i) Based on the multiple hit hypothesis, in order to achieve significant neuroprotection should we combine several drugs to target the major underlying mechanisms? Such pre-clinical research is key but difficult to support financially and to publish in high profile journals. ii) In a given human newborn, can we determine the major pathophysiological mechanism(s) which is (are) at play? iii) Can we design a strategy which can block brain damage without interfering with normal development? iv) Why are drug companies so reluctant to invest in the neonatal field? v) What are the ethical issues associated with clinical trials in neonates?

Selected publications

Verney C, Rees S, Biran V, Thompson M, Inder T, Gressens P. Neuronal damage in the preterm baboon : impact of the mode of ventilatory support. J. Neuropathol. Exp. Neurol., 2010, 69: 473-482.
Olivier P, Loron G, Fontaine RH, Dalous J, Thi HP, Charriaut-Marlangue C, Thomas JL, Mercier JC, Pansiot J, Gressens P, Baud O. Nitric oxide is a key factor for myelination of the developing brain. J. Neuropathol. Exp. Neurol., 2010, 69: 828-837.
Passemard S, El Ghouzzi V, Nasser H, Verney C, Vodjdani G, Lacaud A, Lebon S, Laburthe M, Robberecht P, Nardelli J, Mani S, Verloes A, Gressens P*, Lelièvre V*. VIP blockade disrupts Mcph1-Chck1 signaling leading to microcephaly in mice. J. Clin. Invest., 2011, 121: 3071-3087.
Favrais G, van de Looij Y, Fleiss B, Ramanantsoa N, Bonnin P, Stoltenburg-Didinger G, Lacaud A, Saliba E, Dammann O, Gallego J, Sisonenko S, Hagberg H, Lelièvre V*, Gressens P*. Systemic inflammation disrupts the developmental program of the white matter. Ann. Neurol., 2011, 70: 550-565.

Bertrand Bloch.