Protection of dopaminergic neurons in hemiparkinsonian monkeys by flavouring ingredient glyceryl tribenzoate

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease and this study underlines the significance of a small molecule glyceryl tribenzoate (GTB), a FDA approved food additive, in preventing parkinsonian pathologies in MPTP-induced animal models. The study conducted in MPTP-induced mice demonstrated dose-dependent protection of nigral tyrosine hydroxylase (TH) and striatal dopamine level by GTB oral treatment and the optimum dose was found to be 50 mg/kg/d. In the next phase, the study was carried out in MPTP-injected hemiparkinsonian monkeys, which recapitulate better clinical parkinsonian syndromes. GTB inhibited MPTP-driven induction of glial inflammation, which was evidenced by reduced level of GTP-p21Ras and phospho-p65 in SN of monkeys. It led to decreased expression of inflammatory markers such as IL-1β and iNOS. Simultaneously, GTB oral treatment protected nigral TH cells, striatal dopamine, and improved motor behaviour of hemiparkinsonian monkeys. Presence of sodium benzoate, a GTB metabolite and a FDA-approved drug for urea cycle disorders and glycine encephalopathy, in the brain suggests that the neuroprotective effect imparted by GTB might be mediated by sodium benzoate. Although the mechanism of action of GTB is poorly understood, the study sheds light on the therapeutic possibility of a food additive GTB in PD.

Protection of Mice from Controlled Cortical Impact Injury by Food Additive Glyceryl Tribenzoate

“…Accordingly, although induction of TBI increased glial inflammation in the hippocampus as evident by upregulation of microglial marker Iba1 and astroglial marker GFAP and increase in the expression of inducible nitric oxide synthase (iNOS), oral GTB strongly inhibited and/or normalized astroglial and microglial activation. This is consistent with our recent findings demonstrating suppression of microglial inflammation in an animal model of Huntington disease [17] and hemiparkinsonian monkeys [20] by oral GTB. Several studies have shown that TBI has a major impact on synapse structure and function via a combination of the instant mechanical insult and glial inflammation, ultimately leading to synapse loss.…”

“…Oral GTB protects mice from experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), via upregulation of TGFβ and regulatory T cells [18]. GTB also inhibits microglial activation in a mouse model of Huntington's disease [17] and a monkey model of Parkinson's disease [20]. GTB is used in the pharmaceutical industry as a safe and nontoxic additive in different dosage forms.…”

Nebulization of low-dose aspirin ameliorates Huntington’s pathology in N171-82Q transgenic mice

“…Immunohistochemistry was performed as described earlier [ 36 , 37 ]. Mice were perfused transcardially with 4 % paraformaldehyde and the brains kept in 30 % sucrose solution at 4 °C.…”

Cinnamic acid, a natural plant compound, exhibits neuroprotection in a mouse model of Sandhoff disease via PPARα

“…Glial activation including astrogliosis and microgliosis and other associated neuroinflammation participate in the pathogenesis of several neurodegenerative disorders [ 4 , 10 ], [ 11 ], [ 12 ]. Astrocytes constitute the majority of the glial cells and play a crucial role in brain homeostasis.…”