These data demonstrate that dietary supplementation with scyllo-inositol can increase brain concentrations by a factor of 2-3. A prior study by McLaurin et al found that dietary supplementation with scyllo-inositol by oral gavage, at the same dose used in the present study, lowered both soluble and insoluble Aβ levels in an AD mouse model as well as ameliorated cognitive deficits and plaque burdens (McLaurin et al., 2006
). In another study they found that these effects even occurred in aged AD mice with well advanced symptoms (Fenili et al., 2007
). Whether or not such an increase will have therapeutic effects in humans remains to be seen, however there were some promising signs in our data that other compounds elevated in AD mouse models could be modulated with scyllo-inositol treatment. For instance, prior studies of APP, APP×PS1 and APP×PS2 mouse models showed that there were elevations in taurine, myoinositol and glutamine while there were decreases in glutamate and NAA (Choi et al., 2007
; Choi et al., 2009
; Dedeoglu et al., 2004
; Marjanska et al., 2005
; von Kienlin et al., 2005
). Our data showed, albeit with small sample sizes and younger mice than those studied using MRS previously, trends towards modulation of glutamine, taurine and NAA with scyllo-inositol feeding (see and ). Thus, MRS will likely prove valuable for following such therapeutic trials in mouse models – especially when combined with the behavioral measurements and pathology in the same animals. The ability to relate the direct increase in brain scyllo-inositol levels to the quantitative effects on other molecules in the same MR spectrum will be useful.
Detection of scyllo-inositol is quite a bit more difficult in rodents than in humans. This is because rodents have much more taurine than do humans. The taurine triplet at 3.43 ppm interferes with the scyllo-inositol singlet peak at 3.36 ppm. Nonetheless, using complete simulation of the metabolite spectra, where the intensity of the taurine triplet at 3.43 ppm will be constrained by the taurine multiplet at 3.26 ppm, with a program such as LCModel, it should be possible to quantify the scyllo-inositol peak at 3.36 ppm in vivo
. Since the scyllo-inositol peak is a singlet with a relatively long T2
(ca. 170ms at 4T in humans (Seaquist and Gruetter, 1998
)) it could potentially be detected at an echo time where taurine is nulled, at approximately 70ms. Further, in humans, there is approximately 5-10 times less taurine in the brain than in rodents. In rodents there appears to be considerably less scyllo-inositol than in humans. According to , and the data we presented for wild-type animals the scyllo-inositol concentration is about 100 μM compared to about 500 μM in humans (Michaelis et al., 1993
). Thus, it should be quite easy to identify in humans – especially at 3 or 4T since there are six magnetically equivalent protons for scyllo-inositol.
In a study in a different mutant APP mouse model of AD (TgCRND8) McLaurin and colleagues showed, using gas chromatography and mass spectroscopy, that 10mg/ml of scyllo-inositol in the drinking water increased the scyllo-inositol concentration in whole brain hemisphere samples by a factor of about 7.5 (Fenili et al., 2007
). This is about a 600-fold larger concentration of scyllo-inositol than we used and yet they were only able to elevate scyllo-inositol approximately 2.5 fold higher than we did using the much lower concentration. This suggests that the concentration of scyllo-inositol in the brain is saturated in the Fenili et al. study (Fenili et al., 2007
) – perhaps by limited transport capacity. The brain has approximately a 10 fold higher concentration of scyllo-inositol than plasma, and it appears as if most of the scyllo-inositol comes from the blood into the brain via active transport rather than being synthesized in situ
). Fenili et al. found that the scyllo-inositol was not incorporated into phosphatidylinositol lipids showing it could not substitute for myo-inositol in those pathways and consequently would have less chance of disrupting such metabolism (Fenili et al., 2007
). These data, combined with the lack of side effects at the high doses, suggests that scyllo-inositol supplementation may be quite safe. Our data further suggest that a dose quite a bit lower than that used in the Fenili et al paper (Fenili et al., 2007
) will likely increase brain scyllo-inositol by the same amount. These data also have important implications for continuing human trials since the high dose arms of ELND005 (scyllo-inositol) using 1000-2000 mg 2× per day were stopped due to an unusual number of deaths. Our data suggest that such a high dose will likely not lead to much higher brain levels of scyllo-inositol than can be attained using lower doses such as 250mg/day. MRS studies will prove invaluable in preliminary dose ranging studies for the promising effects of scyllo-inositol treatment in humans.