The vanadium (IV) compound rescues septo-hippocampal cholinergic neurons from neurodegeneration in olfactory bulbectomized mice.
The bilateral olfactory bulbectomy (OBX) mouse exhibits neurodegeneration of cholinergic neurons in the medial septum with concomitant cognitive deficits. Consistent with our previous observations, choline acetyltransferase (ChAT) protein levels in the medial septum decreased by 43.5% 2 weeks after OBX without changes in glutamic acid decarboxylase-65 (GAD65) levels. Interestingly, levels of the vesicular acetylcholine transporter (VAChT), which is localized at cholinergic neuron terminals, decreased both in hippocampal CA1 and CA3 regions following OBX. Confocal microscopy showed that VAChT expression was more severely reduced in CA3 14 days after OBX compared with CA1. Intriguingly, chronic treatment with a vanadium (IV) compound, VO(OPT) [bis(1-N-oxide-pyridine-2-thiolato)oxovanadium(IV)] (0.5-1 mg as vanadium (V)/kg/day, i.p.), significantly rescued cholinergic neurons in the medial septum in a dose-dependent manner. VO(OPT) treatment also prevented decreased VAChT immunoreactivity both in CA1 and CA3 regions in the hippocampus. Consistent with these findings, an impaired hippocampal long-term potentiation (LTP) and memory deficits seen in OBX mice were significantly prevented by VO(OPT) treatment. Taken together, OBX induces neurodegeneration of septo-hippocampal cholinergic neurons and impairment of memory-related behaviors. The neuroprotective effect of VO(OPT) could lead to novel therapeutic strategies to ameliorate cognitive deficits associated with cholinergic neuron degeneration in Alzheimer's disease and other neurodegenerative disorders.
Han
F
F
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan.
Shioda
N
N
Moriguchi
S
S
Qin
Z-H
ZH
Fukunaga
K
K
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009830:Olfactory Bulb / Q000293:injuries* / Q000378:metabolism; D009942:Organometallic Compounds / Q000627:therapeutic use*; D018408:Patch-Clamp Techniques; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
D009942:Organometallic Compounds; D050494:Vesicular Acetylcholine Transport Proteins; C507910:bis(1-N-oxide-pyridine-2-thiolato)oxovanadium(IV); D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D000109:Acetylcholine