Title : Evaluation of the neuroprotective potential of indicaxanthin from opuntia ficus indica fruit against dysmetabolism-related neurodegeneration both in vivo and in vitro
Overnutrition and modern diets containing high proportions of saturated fat are amongst the major factors responsible for the development of low-grade, systemic, chronic inflammation, dyslipidaemia and hyperglycaemia. Interestingly enough, recent studies started to recognize oxidative stress-related glucose dysmetabolism as a risk factor also for neurodegenerative conditions such as Alzheimer’s disease (AD) and other cognitive disorders. Coherently, over 80% of AD patients have T2DM or abnormal serum glucose levels, suggesting that the pathogenic mechanisms of T2D and AD might well overlap in a self-feeding, vicious cycle between chronic neuro-inflammation, mitochondrial dysfunction and oxidative stress. In these scenarios, the molecular interconnections between neuro-inflammation and glucose dysmetabolism could represent a potential therapeutic target to prevent or ameliorate neurodegeneration and cognitive impairment.
Indicaxanthin (Ind) is a bioavailable, betalain pigment from Opuntia ficus indica fruit, able to cross the brain-blood-barrier. Relevantly, the phytochemical has been demonstrated to interfere with redox-dependent signalling pathways, exerting significant anti-oxidative and anti-inflammatory effects both in vivo and in vitro. Recent evidences also demonstrated that a nutritionally-relevant dose of Ind ameliorates glucose dysmetabolism and counteracts IR in a murine model of metabolic syndrome. Along these lines and taking into account the strict interconnections between neurodegeneration, oxidative stress and glucose dysmetabolism, this work has explored whether and how Ind, extracted from Opuntia ficus indica fruit, exerts protective effects in an in vivo model of dysmetabolism-related neurodegeneration.
To this end, Ind was purified as detailed in the Italian Patent Application No. 102021000015167 filed on 10.06.2021. C57BL/6J mice (n=24) were grouped as follows: 1. a negative control group was fed with a standard diet for 14 weeks; 2. a positive control group was fed with a high fat diet (HFD) for 14 weeks; 3. an Ind-group was fed with HFD for 10 weeks and subsequently received Ind per os at a nutritionally relevant dose of 0.86 mg/kg/day for 4 weeks within a HFD regimen. At the end of the treatment, mice were sacrificed, brains rapidly dissected for hippocampus and cortex and neuro-apoptosis, neuro-inflammation and oxidative stress evaluated.
Our results clearly show that Ind treatment significantly counteracted the HFDinduced brain weight reduction and apoptotic nuclei formation (evaluated by TUNEL assay). Moreover, the phytochemical administration also inhibited neuro apoptosis by reducing FasL, Bim, and P27 mRNA levels while increasing the Bcl-2 and BDNF ones (assessed by qRT-PCR). From a mechanistic perspective, Ind-mediated effects on HFD-induced neurodegeneration were associated with a reduction of brain oxidative stress and neuro-inflammation. Indeed, Ind treatment effectively counteracted the HFD-induced RONS, malondialdehyde and NO production, evaluated by spectrofluorimetric and colorimetric assays. Coherently, an increase of the expression levels of Nrf-2 and its downstream activation products HO-1 and SOD-2 was also observed in the Ind-group. Along these evidences, Ind administration also ameliorated neuro-inflammation assessed as expression levels of NF-kB and its downstream activation products iNOS and COX-2 by western blotting.
As a whole, our present results indicate that Ind treatment is able to counteract neurodegeneration in an in vivo model of metabolic syndrome, at a nutritionally relevant dose. Modulation of the expression of crucial genes and proteins involved in the oxidative stress-dependent inflammatory reaction underlying the obesity-related neurodegeneration emerges as a possible mechanism for the observed neuroprotective effects. In perspective, our data suggest a potential employment of Ind, alone or in combo-therapy, to prevent and/or treat neurodegenerative conditions associated to glucose dysmetabolism.
- The neuroprotective effects and mechanisms of Indicaxanthin, a novel, combotherapeutic molecule.
- Relevant information for biochemists, neurologists, nutritionists, pharmacologists.