Neurotoxic effects of AZT on developing and adult neurogenesis.

Azidothymidine (AZT) is a synthetic, chain-terminating nucleoside analog used to treat HIV-1 infection. While AZT is not actively transported across the blood brain barrier, it does accumulate at high levels in cerebrospinal fluid, and subsequently diffuses into the overlying parenchyma. Due to the close anatomical proximity of the neurogenic niches to the ventricular system, we hypothesize that diffusion from CSF exposes neural stem/progenitor cells and their progeny to biologically relevant levels of AZT sufficient to perturb normal cell functions.

Microglia from neurogenic and non-neurogenic regions display differential proliferative potential and neuroblast support.

Microglia isolated from the neurogenic subependymal zone (SEZ) and hippocampus (HC) are capable of massive in vitro population expansion that is not possible with microglia isolated from non-neurogenic regions. We asked if this regional heterogeneity in microglial proliferative capacity is cell intrinsic, or is conferred by interaction with respective neurogenic or non-neurogenic niches. By combining SEZ and cerebral cortex (CTX) primary tissue dissociates to generate heterospatial cultures, we find that exposure to the SEZ environment does not enhance CTX microglia expansion; however, the CTX environment exerts a suppressive effect on SEZ microglia expansion.

In vivo intermittent hypoxia elicits enhanced expansion and neuronal differentiation in cultured neural progenitors.

In vitro exposure of neural progenitor cell (NPC) populations to reduced O(2) (e.g. 3% versus 20%) can increase their proliferation, survival and neuronal differentiation.

Ethynyldeoxyuridine (EdU) suppresses in vitro population expansion and in vivo tumor progression of human glioblastoma cells.

Thymidine analogs (TAs) are synthetic nucleosides that incorporate into newly synthesized DNA. Halogenated pyrimidines (HPs), such as bromodeoxyuridine (BrdU), are a class of TAs that can be detected with antibodies and are commonly used for birthdating individual cells and for assessing the proliferative index of cell populations. It is well established that HPs can act as radiosensitizers when incorporated into DNA chains, but they are generally believed not to impair normal cell function in the absence of secondary stressors.

Transplantation of neural stem/progenitor cells into developing and adult CNS.

Neural transplantation has been a long-standing goal for the treatment of neurological injury and disease. The recent discovery of persistent pools of neural stem cells within the adult mammalian brain has re-ignited interest in transplant therapeutics. Since neural stem cells are self-renewing, it may be possible to culture and expand neural stem cells and their progenitor cell progeny to sufficient numbers for use in autologous, self-repair strategies.