3) ARTICLE - stevia & reward pathway [2011.06.29]

Stevia & Reward Pathway
The miracle of stevia explained from a neuro-scientiphical point of view: the actions on mesencephalic reward pathway.
Stevia, reward pathway, diabetes,
glucosides, diterpenes, metencephalon,
dopamine, VTA

The effect on the mesencephalic reward pathway by many molecules contained in Stevia rebaudiana bertoni, a classically anti-diabetic plant with a central action: glycosides with mainly sweetener function, and diterpenes excitant on the CNS.
Thanks to their actions on the VTA, the isosteviol, stevioside and rebaudioside molecules in particular have hypo-tension and hypo-glycemic effects that benefit both diabetic and dismetabolism dysfunction patients and healthy people as well, given that they are nootropic.
Stevia rebaudiana bertoni is a herbaceous plant in the Asteraceae family, originally from an area between Paraguay and Brasil, that grows to a height of 80 cm when fully matured and has green oblong toothed leaves with small and white flowers.
Its properties were known to South American natives, who used it as sweetener, while also enjoying its relaxing anti-hypertensive effects. The first scientist to describe the properties of its leaves was the Paraguaian botanic Bertoni in 1887; leaves had some effects:
- Hypo-tension inducing but also energizing
- Hypo-glycemic with glucide homeostasis regulation
- digestive
- re-equilibrator of the skin and mucosae (and of entire oral system, with the prevention of caries for example)
Stevia is by now considered one of the best existing medical herbs. In the city of Birigui they talk of the “miracle of stevia” thanks to its therapeutic properties against diabetes, hypertension, and various infections, with the creation of a real local market involving also bars and restaurants: stevia is also used in infusions and also as basal sweetener.
A chemical analysis of the plant’s chemical compound shows:
- Glucosides (sweeteners): stevioside (a-3), rebaudioside (AF), dulcoside (AB).
- Diterpenes (excitant on CNS): steviosides, rebaudiosides, isosteviol.
- Flavonoide, vitamins A and C.
After excluding all possible toxicity, studies [5] have identified numerous properties: antihypertensive, tonic over heart (thanks to glycosides similar to digitalic ones), anti-diabetic and central sweetener:
- stevioside acts as a typical systemic vasodilator, determining hypotension, natriuresis and diuresis with an increase in GFR, due to its hypo-tension qualities [6]
- stevioside acts directly on beta-cell determining insulin secretion [7, 8], because it is anti-hyperglycemic and hypo-glycemic [9]; at the molecular level it has been demonstrated by underlying as the molecule activates acetilCoA carboxilase and the expression of ACC gene, both involved in a secretion that is qualitatively and quantitatively better of insulin from beta-cell, thanks to K+-ATP channel normally helped by receptors for sulfanilureae [10]
- being diterpenes, stevioside and rebaudioside have effects in the central nervous system and a sweetening power 300 times more than sugar, function due to their neurotransmitting essence; this means a reduction in the sensation of hunger with beneficial effects mostly for patients with diabetes and obesity thanks to which property the Loanio University-2004 International Symposium acclaimed their use as sweeteners, being already used as integrators in 1995 in USA
- isosteviol, with mainly a diterpenic action, was shown to modify the expression of genes regulating insulin (GLUT2, Ins1, Ins2,…) and determining an up-regulation in the expression of the genes of beta-cells and the successive improvement of both sensitivity to glucose and the lipid profile [11].
The situation is characterized by the many functions played by diterpenic glycosides, which stimulate insulin sensitivity with a direct action on beta-cells thanks to genic up-regulation, with a consequent increase in the quantity of insulin; this leads to a re-organization of the glycemic metabolism at a peripheral level.
The greatest effect is on VTA. The rise in insulin and genic re-equilibrium reduce insulin-resistance and rehabilitate the reward function, with a relative increase in dopamine.
The effect of stevia on the reward mesencephalic mechanism is mainly achieved by its diterpenes stevioside, rebaudioside and isosteviol, which reveal themselves to be nootropic molecules. Diterpenes are molecules that are intrinsically capable of directly acting on the dopaminergic system [12]: they are formed by four unities of isoprenes with a complexive formula C20H32, and their action consists in increasing adenilil-cyclasic activity with final dopaminergic stimulation.
The analogy may be seen in the molecular action of steviosides: in the same way in which they link sulfanilureae receptors associated on the plasmatic membrane of pancreatic beta-cells at K+ ATP dependent channels with consequent closure of the K+ channel, depolarization, entrance of Ca++ and insulin secretion (even if it has been shown that insulin secretion is induced also directly [8]), in fact, diterpenic glycosides inhibit (in roughly the same way as digitalis on miocyte) Na+/K+/ATPase with relative increase in intracellular Na+ and electrochemical balances so to create an increase in dopamine [12].
The increase in dopamine is therefore the basis for a resumption of the reward mechanisms that take place in mesencephalic VTA.
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