Behavioral alterations in Lewis rats following two-day continuous 3-nitropropionic acid administration.

The mitochondrial toxin, 3-nitropropionic acid (3-NP), produces motor dysfunction and striatal atrophy in rats. However, rat strain and method of administration may contribute to variability in the deficits caused by 3-NP toxicity. To evaluate this, changes in nocturnal spontaneous locomotor activity from chronic administration of 3-NP using an osmotic mini pump, were examined in the Lewis rats. Lewis rats were treated with 3-NP or saline for 2 days and behavior was tested daily for a 15 day period. Animals receiving 3-NP displayed significantly less spontaneous activity than animals in the saline group. 3-NP treated animals also weighed significantly less when compared to saline treated animals. These results demonstrate that even though there were no significant alterations in overt anatomical pathology, even short-term exposure to 3-NP produced significant effects. This short-term administration may present a potential paradigm for examination of sub-threshold neurotoxicity.

Do hematopoietic cells exposed to a neurogenic environment mimic properties of endogenous neural precursors?

Hematopoietic progenitors are cells, which under challenging experimental conditions can develop unusual phenotypic properties, rather distant from their original mesodermal origin. As previously reported, cells derived from human umbilical cord blood (HUCB) or human bone marrow (BM) under certain in vivo or in vitro conditions can manifest neural features that resemble features of neural-derived cells, immunocytochemically and in some instances also morphologically. The present study explored how hematopoietic-derived cells would respond to neurogenic signals from the subventricular zone (SVZ) of adult and aged (6 and 16 months old) rats. The mononuclear fraction of HUCB cells was transplanted into the SVZ of immunosuppressed (single cyclosporin or three-drug treatment) animals. The triple-suppression paradigm allowed us to protect transplanted human cells within the brain and to explore further their phenotypic and migratory properties. One week after implantation, many surviving HUCB cells were located within the SVZ and the vertical limb of the rostral migratory stream (RMS). The migration of HUCB cells was restricted exclusively to the pathway leading to the olfactory bulb. In younger animals, grafted cells navigated almost halfway through the vertical limb, whereas, in the older animals, the migration was less pronounced. The overall cell survival was greater in younger animals than in older ones. Immunocytochemistry for surface CD antigen expression showed that many HUCB cells, either cultured or within the brain parenchyma, retained their hematopoietic identity. A few cells, identified by using human-specific antibodies (anti-human nuclei, or mitochondria) expressed nestin and doublecortin, markers of endogenous neural progenitors. Therefore, it is believed that the environment of the neurogenic SVZ, even in aged animals, was able to support survival, "neuralization," and migratory features of HUCB-derived cells.

Lack of NF-kappaB p50 exacerbates degeneration of hippocampal neurons after chemical exposure and impairs learning.

The roles of activated NF-kappaB subunits in the CNS remain to be discerned. Members of this family of transcription factors are essential to diverse physiological processes and can be activated by pathogens, stress, pharmacological agents, and trauma. We are particularly interested in long-term NF-kappaB activation and its involvement in neuroplastic changes in the brain resulting from acquisition of memory as well as injury. Here, we use lesioning by the limbic-specific neurotoxicant trimethyltin (TMT) as a model in which to examine activation of the NF-kappaB p50 subunit before, during, and after neuronal degeneration. Neurons in wild-type mice that survived TMT-induced injury contained activated p50 and did not label with Fluoro-Jade, a histochemical marker of degenerating neurons. Granule cells of the wild-type dentate gyrus subregion, an area particularly vulnerable to TMT-induced degeneration, contained less activated p50 protein than CA regions. We compared the extent of degeneration in wild-type and p50-null mice and found a fivefold increase in death of hippocampal neurons in mice lacking p50. The hippocampus is key to processes of learning and memory, and NF-kappaB has reported involvement in these processes. The enhanced hippocampal degeneration in p50-null mice prompted us to evaluate their basal learning abilities, and we discovered that difficulties in task acquisition were an additional consequence of p50 ablation. These results indicate that absence of p50 negatively modulates learning ability as well as hippocampal responsiveness to brain injury after a chemical-induced lesion.

Intraspinal implantation of hNT neurons into SOD1 mice with apparent motor deficit.

INTRODUCTION: The aim of this study was to determine the effect of hNT neuron transplants on motor neuron function in SOD1 (G93A) mice when motor deficits were already apparent. METHOD: The hNT neurons were implanted into L(4)-L(5) segments of the ventral horn spinal cord of mice at 15-16 weeks of age: either G93A mice, transgenic mice carrying the normal allele for human SOD1 gene (hTg), or control wild type mice (wt). Behavioral tests (rotorod, beam balance, extension reflex, footprint) were performed prior to transplantation and at weekly intervals afterwards. RESULTS: HNT neuron transplantation in the SOD1 mice delayed disease progression for 3-4 weeks, although lifespan was not affected. CONCLUSION: These results suggest that hNT neuron transplantation may be a promising therapeutic strategy for ALS in the later phase of the neurodegeneration.

hNT neurons delay onset of motor deficits in a model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that manifests as a progressive muscular weakness leading to paralysis and death. Because of the diffuse nature of the motor neuron death, this disease is not considered a good candidate for treatment through neural transplantation. The purpose of this study was to show that transplantation of human neuron-like cells (hNT neurons) into the spinal cord of a transgenic ALS mouse model would improve motor deficits. The hNT neurons were transplanted bilaterally into L4-L5 spinal cord of the transgenic mice ( approximately 8 weeks of age), and the animals were evaluated on health and behavioral measures. The animals were perfused, and immunohistochemistry was performed to identify the transplanted cells. Transplantation of the hNT neurons into the spinal cord delayed the onset of motor behavioral symptoms. This was the first demonstration that even localized transplantation of neural cells directly into the parenchyma could improve motor function in an ALS model. Further study is needed to delineate the mechanism underlying these effects. This therapeutic approach has the potential to restore neural transmission, thereby improving quality of life for the ALS patient and possibly extend life expectancy.