GROWTH FACTORS AND NEUROPROTECTION OF THE PERINATAL BRAIN

Objectives: Pharmacological neuroprotective strategies can clearly stop lesions from getting worse, but agents which have neurotrophic properties can also affect repair in a developing brain. Although prevention and treatment at early stages of brain lesions are mostly desirable, post-lesion plasticity is the only affordable target in many cases, due to the lack of early detectors of perinatal brain lesions.

Methods & Results: This has been shown in excitotoxic models of neonatal white matter damage (WMD) for melatonin. Although melatonin did not prevent the initial appearance of WMD, it did promote secondary lesion repair with axonal regrowth and/or sprouting. Behavioral studies support the hypothesis that melatonin-induced white matter histological repair is accompanied by improved learning capabilities at adulthood. Melatonin is a safe compound, including in term newborns, although its use has rarely been evaluated in controlled trials. Melatonin derivatives which are under development and tested in controlled clinical trials could make this latter statement obsolete.

In a similar excitotoxic model of neonatal WMD, post-lesion plasticity was also induced by brain-derived neurotrophic factor (BDNF). However, the clinical use of BDNF is actually limited by its low capacity to cross the blood-brain barrier and by its central role in multiple steps of brain development, raising concerns about its direct use in newborns. Potential alternatives are either agents, such as ampakines (positive allosteric modulators of AMPA receptors) or vasoactive intestinal peptide (VIP), which can cross the blood-brain-barrier and increase BDNF production, or BDNF-expressing viral vectors which can increase BDNF production over a protracted period of time following a single intracerebral injection. These agents were shown experimentally to mimic the neuroprotective properties of BDNF.

Conclusion: Although promising these data require to be confirmed in other preclinical models and to be accompanied by data showing a gain of function.

Keywords: BDNF, excitotoxicity, glutamate, melatonin, neurotrophin, plasticity, VIP