br Results br Discussion Drug

Results
Discussion Drug therapy for the H/I-injured BMN673 has focused largely on anti-oxidants (allopurinol, N-acetylcysteine), anti-excitotoxic agents (topiramate, memantine), and anti-inflammatory agents (cromolyn) (Juul and Ferriero, 2014; Hagberg et al., 2015). These therapies have been shown to primarily mediate their effects through neuroprotection and have resulted in varying degrees of functional recovery and a reduction in infarct volume. Further, while they display similarities in cost-effectiveness, implications in different injury models, and success in adults or old age animals, metformin is the only drug treatment that has demonstrated efficacy in generating new cells in the neonatal brain. Metformin may confer additional advantages such as improving lifespan (Martin-Montalvo et al., 2013) and promoting angiogenesis (Jin et al., 2014; Liu et al., 2014; Venna et al., 2014). The finding that metformin, an anti-diabetic drug, increases the absolute number of NPCs following injury (rather than changing the relative percentage of differentiated cells) was surprising. Several possibilities could account for this observation. For example, metformin could have direct effects on NPCs (such as changes in cell-cycle kinetics and/or promoting cell survival) or indirect effects on non-NPCs that leads to the release of growth/trophic factors, providing immunomodulation, neuroprotection, and/or angiogenesis, which could effectively lead to an expansion in the size of the NPC pool. Indeed with respect to the latter, recent studies using chronic metformin treatment in adult ischemia models have demonstrated enhanced angiogenesis/neurogenesis correlating with motor function recovery (Jin et al., 2014; Liu et al., 2014). Given that the developing brain is known to exhibit a greater degree of plasticity (Kolb and Gibb, 2011) and a greater number of resident NPCs compared to the adult brain (Sachewsky et al., 2014), it is plausible that similar mechanisms of enhanced angiogenesis and neurogenesis are occurring in our H/I injury model.
Experimental Procedures
Author Contributions
Acknowledgments
Introduction Multiple system atrophy (MSA) and Parkinson’s disease (PD) are adult-onset progressive neurodegenerative diseases that are hallmarked at the cellular level by the presence of alpha-synuclein (ΑSYN) protein containing inclusions. Interestingly, the inclusions are found in neurons in PD, where the SNCA gene encoding for ASYN protein is expressed, whereas they are prominent in oligodendrocytes as glial cytoplasmic inclusions (GCIs) in MSA (Papp et al., 1989; Stefanova et al., 2009). Because strong evidence showing that oligodendrocytes in the adult brain are capable of expressing SNCA is lacking, recent studies inspired from parkinsonian experimental models have proposed the interesting hypothesis that ASYN present in GCIs in MSA could be of neuronal origin and transfer to oligodendrocytes (Kisos et al., 2012; Reyes et al., 2014), where it would accumulate and potentially lead to oligodendrocyte dysfunction. However, more than a decade ago, Richter-Landsberg and coworkers reported on the transient expression of Snca in cultures enriched in oligodendrocytes, prepared by mechanical shaking of mixed rat glial primary brain cultures (Richter-Landsberg et al., 2000). This finding, however, was neither confirmed nor further explored, and in vivo evidences of ASYN expression during oligodendrocyte maturation are still missing. Consequently, follow-up studies mainly focused on understanding the functional consequences of wild-type or mutant human ASYN targeted expression in oligodendrocytes in experimental models in vivo and in vitro (Kragh et al., 2013; Yazawa et al., 2005). To date, the origin of ASYN in GCIs in oligodendrocytes in MSA is still elusive, as is that of the few inclusions found in glial cells in the substantia nigra of people with PD (Wakabayashi et al., 2000). For these reasons, ASYN expression in oligodendrocytes remains to be firmly established, especially since investigations using patient material are still controversial (Asi et al., 2014; Miller et al., 2005). One way to explore ASYN expression in human oligodendrocytes is through the generation of human cellular models such as induced pluripotent stem cells (iPSCs), since patient oligodendrocytes are not always accessible postmortem.