Cinnamon and Its Metabolite Sodium Benzoate Attenuate the Activation of p21rac and Protect Memory and Learning in an Animal Model of Alzheimer’s Disease

Abstract

This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in attenuating oxidative stress and protecting memory and learning in an animal model of Alzheimer’s disease (AD). NaB, but not sodium formate, was found to inhibit LPS-induced production of reactive oxygen species (ROS) in mouse microglial cells. Similarly, NaB also inhibited fibrillar amyloid beta (Aβ)- and 1-methyl-4-phenylpyridinium(+)-induced microglial production of ROS. Although NaB reduced the level of cholesterol in vivo in mice, reversal of the inhibitory effect of NaB on ROS production by mevalonate, and geranylgeranyl pyrophosphate, but not cholesterol, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the antioxidant effect of NaB. Furthermore, we demonstrate that an inhibitor of p21rac geranylgeranyl protein transferase suppressed the production of ROS and that NaB suppressed the activation of p21rac in microglia. As expected, marked activation of p21rac was observed in the hippocampus of subjects with AD and 5XFAD transgenic (Tg) mouse model of AD. However, oral feeding of cinnamon (Cinnamonum verum) powder and NaB suppressed the activation of p21rac and attenuated oxidative stress in the hippocampus of Tg mice as evident by decreased dihydroethidium (DHE) and nitrotyrosine staining, reduced homocysteine level and increased level of reduced glutathione. This was accompanied by suppression of neuronal apoptosis, inhibition of glial activation, and reduction of Aβ burden in the hippocampus and protection of memory and learning in transgenic mice. Therefore, cinnamon powder may be a promising natural supplement in halting or delaying the progression of AD.

Cinnamon Converts Poor Learning Mice to Good Learners: Implications for Memory Improvement

“…While NaB and NaFO were solubilized in water, cinnamon ( Cinnamonum verum ) powder was mixed in 0.5% methylcellulose (MC). Mice were gavaged 100 μL cinnamon-mixed MC and 100 μL NaB- and NaFO-mixed water once daily using gavage needle as described (Jana et al, 2013; Khasnavis and Pahan, 2014; Mondal and Pahan, 2014; Modi et al, 2015). Another group of control mice also received only MC as vehicle.…”

“…Barnes maze was performed as described by us (Corbett et al, 2013; Roy et al, 2013; Modi et al, 2014; Modi et al, 2015). Briefly, for Barnes maze, mice were trained for 2 consecutive days followed by examination on day 3.…”

“…T maze experiments were performed as described by us (Roy et al, 2013; Modi et al, 2014; Modi et al, 2015). Briefly, mice were habituated in the T-maze for two days under food-deprived conditions so that animals can eat food rewards at least five times during 10 minutes period of training.…”

“…We have already demonstrated that after oral administration, cinnamon is metabolized into sodium benzoate (NaB), a food-additive and an FDA-approved drug for hyperammonemia, and that the level of NaB increases in different parts of the brain after cinnamon intake (Jana et al, 2013; Modi et al, 2015). We have also delineated that NaB is anti-inflammatory (Brahmachari et al, 2009), immunomodulatory (Brahmachari and Pahan, 2007), neurotrophic (Jana et al, 2013), anti-oxidant (Modi et al, 2015), and neuroprotective (Jana et al, 2013). Here, we delineate that NaB stimulates calcium influx via NMDA- and AMPA-sensitive ionotropic glutamate receptors, increases the expression of plasticity related molecules and enhances morphological plasticity in hippocampal neurons.…”

Upregulation of Suppressor of Cytokine Signaling 3 in Microglia by Cinnamic Acid

“…Although we have demonstrated beneficial effect of whole cinnamon powder in animal models of multiple sclerosis (50), Parkinson’s disease (51) and Alzheimer’s disease (52), some brands of cinnamon (e.g. Cinnamonun cassia ) contains coumarin, a hepatotoxic molecule.…”