Neurotrophic effects of Cerebrolysin in the Mecp2308/Y transgenic model of Rett syndrome

Abstract

Rett syndrome is a childhood neurodevelopmental disorder caused by mutations in the gene encoding for methyl CpG binding protein (MeCP2). Neuropathological studies in patients with Rett syndrome and in MeCP2 mutant models have shown reduced dendritic arborization and abnormal neuronal packing. We have previously shown that Cerebrolysin (CBL), a neurotrophic peptide mixture, ameliorates the synaptic and dendritic pathology in models of aging and neurodegeneration. This study aimed to determine whether CBL was capable of reducing behavioral and neuronal alterations in Mecp2 308/Y mutant mice. Two sets of experiments were performed, the first with 4 month old male Mecp2 308/Y mutant mice treated with CBL or vehicle for 3 months (Group A) and the second with 1 month old mice treated for 6 months (Group B). Behavioral analysis showed improved motor performance with CBL in Group A and a trend toward improvement in Group B. Consistent with behavioral findings, neuropathological analysis of the basal ganglia showed amelioration of dendritic simplification in CBL-treated Mecp2 308/Y mutant mice. CBL treatment also ameliorated dendritic pathology and neuronal loss in the hippocampus and neocortex in Mecp2 308/Y mutant mice. In conclusion, this study demonstrates that CBL promotes recovery of dendritic and neuronal damage and behavioral improvements in young adult Mecp2 308/Y mutant mice and suggests that CBL may have neurotrophic effects in this model. These findings support the possibility that CBL may have beneficial effects in the management of Rett syndrome.

Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer's disease

“…Although the most significant effects of CBL in the hAPP tg mice were on NGF, we also detected increased expression of GDNF. This, in combination with the CNTF‐ and FGF‐like effects of CBL and its peptide derivatives (Chen et al, 2007; Blanchard et al, 2010a, b; Chohan et al, 2011; Rockenstein et al, 2011a), might account for the neurotrophic effects of CBL in other brain regions such as the hippocampus and the neocortex (Doppler et al, 2008).…”

Combined administration of cerebrolysin and donepezil induces plastic changes in prefrontal cortex in aged mice

“…In agreement with the present results, i.p. administration of Cbl enhanced DG neurogenesis, synaptophysin immunoreactivity, and density of glutamate receptor subunit 1 in hippocampus and improved the spatial learning and memory of aged rats (Eder et al,2001; Francis‐Turner and Valousková,1996; Gschanes and Windisch,1999; Reinprecht et al,1999; Tatebayashi et al,2003), reduced the amyloid burden in the frontal cortex of 5‐month‐old APP transgenic mice (Rockenstein et al,2006) and improved the motor function in rats and transgenic mice (Doppler et al,2008; Sharma et al, 2010).…”

Cerebrolysin treatment attenuates heat shock protein overexpression in the brain following heat stress

“…15–18). Alternatively, Cerebrolysin treatment may alter the cellular and molecule response of microvessels to these neurochemicals leading to less disruption of the BBB in heat stress 19,20 …”

“…Alternatively, Cerebrolysin treatment may alter the cellular and molecule response of microvessels to these neurochemicals leading to less disruption of the BBB in heat stress. 19,20 Extravasation of proteins into the CNS microfluid environment leads to vasogenic edema formation. [21][22][23] The increase in brain water content in the areas showing disruption of the BBB to Evans blue and radioiodine found in the present investigation further supports this hypothesis.…”