Substance P is a promoter of adult neural progenitor cell proliferation under normal and ischemic conditions

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  • 1 Department of Neurological Surgery
  • 3 Neuroscience Training Program
  • 4 Cardiovascular Research Center, and
  • 5 Regenerative Medicine Program, University of Wisconsin-Madison, Wisconsin; and
  • 2 Department of Neurological Surgery, Chung-Ang University, Seoul, Korea
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Object

Neurogenesis continues throughout the life of mammals in the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus (DG) of the hippocampus. The authors tested the potential of the neuropeptide substance P (SP) acting via the neurokinin-1 receptor (NK1R) in promoting the proliferation of adult rat neural progenitor cells (NPCs).

Methods

Focal ischemia was induced in spontaneously hypertensive rats by transient middle cerebral artery occlusion. Substance P and the NK1R antagonist L-703,606 were infused into the lateral ventricles of rats by using Alzet osmotic minipumps. Progenitor cell proliferation was evaluated with immunostaining for bromodeoxyuridine (BrdU) and immature neural marker doublecortin (DCX). Neurospheres were cultured from the SVZ of adult rats.

Results

Under in vitro conditions, SP (0.01–10 μmol/L) increased the proliferation of cultured NPCs, with a peak increase of 52 ± 7% at 0.1 μmol/L. Substance P (0.1 μmol/L) continuously increased NPC proliferation from 6 hours to 5 days, which was prevented by L-703,606 (by 69–98%). The cultured NPCs expressed both SP and NK1R proteins, indicating that these effects are receptor specific. Continuous infusion of SP (1 μmol/L) into the lateral ventricles for 5 days significantly increased the number of proliferating NPCs (cells positive for both BrdU and DCX) in both the SVZ (by 173 ± 24%, p < 0.05) and DG (by 82 ± 12%, p < 0.05) in adult rats; however, infusion of L-703,606 (10 μmol/L) significantly prevented the postischemic induction of NPC proliferation in both the SVZ (by 84 ± 6%, p < 0.05) and DG (by 63 ± 7%, p < 0.05).

Conclusions

Data in these studies indicated that SP plays a role in normal and ischemia-induced neurogenesis in the adult brain and thus could help central nervous system plasticity following injury.

Abbreviations used in this paper:ACSF = artificial cerebrospinal fluid; BDNF = brain-derived neurotrophic factor; BrdU = bromode-oxyuridine; DCX = doublecortin; DG = dentate gyrus; Ig = immunoglobulin; MCAO = middle cerebral artery occlusion; MTS = 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophen yl)-2H-tetrazolium; NK1R = neurokinin-1 receptor; NPC = neural progenitor cell; PBS = phosphate-buffered saline; SD = standard deviation; SP = substance P; SVZ = subventricular zone; TBS = Tris-buffered saline.

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Contributor Notes

Address reprint requests to: Robert J. Dempsey, M.D., Department of Neurological Surgery, University of Wisconsin-Madison, 600 Highland Avenue, Madison, Wisconsin 53792. email: dempsey@neurosurg.wisc.edu.
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