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Rett syndrome (RTT) is a postnatal, severe, disabling neurodevelopmental disorder occurring almost exclusively in females and is the second most common cause for genetic mental retardation in girls. In the majority of cases it is caused by mutations in gene (MECP2) encoding methyl-CpG-binding protein 2. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor playing a major role in neuronal survival, neurogenesis and plasticity. Animal studies suggested that abnormalities in BDNF homeostasis may contribute to the pathogenesis in Mecp2 null mice, and BDNF administration in the Mecp2 mutant brain led to later onset/slower disease progression, suggesting that increased BDNF in the brain could be therapeutic for this disease. Mature BDNF is a 14 kDa protein that may have poor blood-brain barrier penetrability. However, recent animal studies demonstrated that peripheral administration of BDNF, either by intravenous injection or intranasal delivery, could increase BDNF levels in the brain. Thus it is proposed that peripheral administration of BDNF in the early stage could have therapeutic potential for RTT subjects. Furthermore, the combination use of mannitol may temporarily open the blood-brain barrier and facilitate the entry of BDNF into brain. The potential therapeutic effect of peripheral BDNF administration could be tested in RTT animal models such as Mecp2 KO mice, which may provide a new intervention for this devastating disease.

Peripheral administration of brain-derived neurotrophic factor to Rett syndrome animal model: A possible approach for the treatment of Rett syndrome