Rationale and Objectives
This study is aimed at investigating neurochemical changes in scopolamine (SCP)–induced memory impairment using spatially localized in vivo magnetic resonance spectroscopy (MRS) of the hippocampus.
Materials and Methods
Four groups of mice (eight mice per group) were scanned after the injection of different SCP doses: 0, 1, 3, and 5 mg/kg (intraperitoneally). All the animals received 1 H MRS of their hippocampus at two time intervals: 30 minutes and 72 hours after SCP injection.
Results
This work demonstrated that the doses of 3 mg/kg SCP or higher reduce the concentration of total choline–containing compounds, and these levels returned to baseline after 72 hours. These results are consistent with observations made by others using more invasive brain dialysis approaches. The levels of glutamate and glutamic compounds (glutamate + glutamine) were slightly changed at 3 and 5 mg/kg SCP dose, but the differences were not statistically significant ( P > .05). These findings suggest that SCP produces transient, in vivo measurable alterations in the cholinergic system in the hippocampus.
Conclusions
On this basis, we conclude that in vivo MRS is a feasible noninvasive method to probe aspects of the alterations induced by SCP in the cholinergic neurotransmission pathways in both animal models and human studies of memory impairment.
Cholinergic deficiency in human brain is the most severe and consistent biochemical change in mild cognitive impairment (MCI) and Alzheimer disease (AD) . This is seen as reduced levels of acetylcholine (ACh), choline acetyltransferase, and acetylcholinesterase reported in both necropsy brain samples and cerebrospinal fluid. In general, animal models of memory impairment have been used to understand the molecular basis of cognitive decline and identify therapeutic targets. Scopolamine (SCP), which is known as a muscarinic cholinergic receptor antagonist, has been used to induce memory deficit/amnesia such as is present in MCI and AD. SCP inhibits central cholinergic neuronal activity and impairs learning and short-term memory . Numerous studies have tried to find treatments that attenuate the effects of SCP-induced memory impairment . Several studies reported that the mechanism of memory impairment by cholinergic deficits may be through the modulation of the cerebrovasculature and decreased blood flow and blood volume may induce rapid cognitive decline . Although the precise molecular details and the influence of SCP on neurometabolic pathways have not been completely elucidated, SCP has been used widely to produce animal models of memory impairment.
The development of spatially localized in vivo proton magnetic resonance spectroscopy ( 1 H MRS) of the brain has led to both mechanistic studies of brain metabolism in animal models of disease and numerous clinical studies of human diseases and their progression . 1 H MRS is well suited for the study of cognitive disorders, because it is noninvasive, reproducible, and can sample the in vivo metabolism of many brain regions. At present, ∼20 compounds can be detected on 3T and 7T whole body magnetic resonance (MR) scanners. Some of these compounds are neurotransmitters . In particular, a resonance reflecting a composite peak representing total choline–containing compounds (tCho) is one of important metabolites in 1 H MRS studies of memory impairment. Some studies have reported that total choline signal in 1 H MRS has been changed in MCI and AD patients . This total choline peak is made up of ACh, glycerophosphocholine (GPC), phosphocholine (PC), and free choline .
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Materials and methods
Animals and Drugs
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Proton Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy
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Quantification
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Analysis
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Results
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Table 1
SNR and CRLBs in Corresponding SCP Dose of Each Group
SCP Dose (mg/kg) CRLB SNR Glutamine Glutamate Amino acid Myo-inositol Taurine tCho tNAA Total creatine 0 30 m 16.88 ± 3.72 7.25 ± 1.58 7.50 ± 1.60 5.75 ± 1.16 4.63 ± 1.19 5.13 ± 0.99 6.50 ± 1.20 3.38 ± 0.74 10.13 ± 1.73 72 h 14.75 ± 3.45 7.38 ± 2.00 7.00 ± 1.41 5.38 ± 0.92 4.25 ± 0.46 5.00 ± 1.51 6.50 ± 2.00 3.13 ± 0.35 10.38 ± 1.85 1 30 m 17.88 ± 4.52 7.38 ± 2.13 7.75 ± 1.90 5.88 ± 1.13 4.50 ± 1.07 4.63 ± 0.74 6.38 ± 1.51 3.13 ± 0.35 10.50 ± 2.00 72 h 16.75 ± 5.70 7.25 ± 1.83 7.38 ± 2.00 5.63 ± 1.30 4.37 ± 1.30 5.00 ± 1.31 6.25 ± 2.05 3.00 ± 0.76 11.00 ± 2.51 3 30 m 18.50 ± 2.07 8.25 ± 2.19 8.50 ± 1.69 6.63 ± 1.85 4.50 ± 0.75 6.38 ± 2.00 7.25 ± 1.67 3.13 ± 0.35 11.63 ± 1.30 72 h 18.50 ± 5.50 8.13 ± 2.64 8.13 ± 2.64 5.75 ± 1.16 5.00 ± 1.77 5.38 ± 1.41 6.88 ± 2.42 3.50 ± 0.76 10.75 ± 1.83 5 30 m 17.63 ± 5.42 8.38 ± 2.50 8.25 ± 2.25 6.13 ± 0.99 4.75 ± 1.91 6.50 ± 1.77 7.38 ± 2.26 3.50 ± 0.76 10.13 ± 1.13 72 h 19.13 ± 6.98 8.00 ± 2.62 8.25 ± 2.71 6.25 ± 1.04 4.88 ± 1.81 5.38 ± 0.92 7.50 ± 2.14 3.38 ± 0.74 9.38 ± 1.60
CRLBs, Cramer–Rao lower bounds; h, hours; m, minutes; SCP, scopolamine; SNR, signal-to-noise ratio; tCho, total choline–containing compounds; tNAA, total N-acetylaspartate.
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Discussion
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Acknowledgments
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