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Transplanted neural precursor cells remyelinate efficiently acutely demyelinated focal lesions. However, the clinical value of cell transplantation in a chronic, multifocal disease like multiple sclerosis will depend on the ability of transplanted cells to migrate to the multiple disease foci in the brain. Here, we expanded newborn rat neural precursor cells in spheres and transplanted them intracerebroventricularly or intrathecally in rats. The cells were labeled by the nuclear fluorescent dye Hoechst or by incubation with BrdU to enable their identification at 2 days and 2 weeks after transplantation, respectively. Spheres consisted of PSA-NCAM(+), nestin(+), NG2(-) undifferentiated precursor cells that differentiated in vitro into astrocytes, oligodendrocytes, and neurons. Spheres that were transplanted into intact rats remained mostly in the ventricles or in the spinal subarachnoid space. Following transplantation at peak of experimental autoimmune encephalomyelitis, cells migrated into the brain or spinal cord parenchyma, exclusively into inflamed white matter but not into adjacent gray matter regions. After 2 weeks, many transplanted cells had migrated into distant white matter tracts and acquired specific markers of the astroglial and oligodendroglial lineages. Thus, the inflammatory process may attract targeted migration of transplanted precursor cells into the brain parenchyma.

Overproduction of interleukin-1 within the brain is associated with Alzheimer's disease and other neurological conditions. We report that peripheral administration of the acetylcholinesterase inhibitors tacrine, rivastigmine, neostigmine, or EN101 (an antisense oligonucleotide directed at acetylcholinesterase messenger RNA) to mice significantly attenuated the production of interleukin-1beta in the hippocampus and blood, concomitantly with the reduction in acetylcholinesterase activity. These findings demonstrate that cholinergic enhancement produces central and peripheral antiinflammatory effects and suggest a novel therapeutic mechanism for acetylcholinesterase inhibitors.

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