Efeitos da curcumina sobre células neurais, diferenciação neural e sinalização purinérgica em embriões de camundongos com toxoplasmose

Abstract

Toxoplasmosis is a parasitic disease caused by the obligate intracellular protozoan Toxoplasma gondii. Its characteristics of encystment and persistence, preferably in the central nervous system of mammals, are worrying, in addition to placental transmission deserves attention due to the possibility of causing miscarriages, malformations and behavioural disturbances. Brain development during embryogenesis is highly compromised by parasite, interfering with cell quantity, migration and differentiation of neural precursor cells. The role of the purinergic system in immune defence and neuroprotection in toxoplasmosis has been gaining attention, in addition to the fact that purinergic components are found during neurogenesis. Despite the serious pathogenicity of the parasite, with a wide distribution worldwide and a high prevalence of vertical transmission, there are no effective therapies in the chronic phase of the disease, as available drugs do not act on tissue cysts. The problems presented and the epidemiological data motivate this study and the search for new therapies to minimize the damage caused by the parasite in congenital infection, here we propose the use of curcumin as a possible treatment. Curcumin is a polyphenol found in higher concentrations in the roots of the Curcuma longa plant and is widely used in scientific literature due to its antioxidant and anti-inflammatory properties, in addition to its neuroprotective action in disorders involving the central nervous system and promising results in a few studies on toxoplasmosis. Despite these beneficial characteristics, curcumin has low bioavailability, with rapid metabolism and certain toxicity, mainly seen at the hepatobiliary and reproductive systems. In the case of the central nervous system, no studies are demonstrating safe concentrations/doses in healthy models. Since our general objective was to evaluate the effects of curcumin on purinergic signalling and neurogenesis of neural precursor cells in the telencephalon of embryos from infected and uninfected mice with Toxoplasma gondii, first of all, it was essential to study the impact of the use of this polyphenol and two curcumin nanocapsules in cells originating from the central nervous system. Exposure of treatments in microglia and neuron cell lines revealed that concentrations between 1-5 μM of curcumin, NC-PCL, and NC-EDG can be used in in vitro models of brain diseases, as they do not significantly affect cell homeostasis. Given this finding, we continued with the isolation of neural precursor cells infected with the VEG strain of Toxoplasma gondii. Our results complement the parasite interference in neural differentiation, but the use of curcumin was able to restore gliogenesis and further increase neurogenesis, with cell size recovery. Changes in the expression of purinergic receptors were also seen in the infection, the use of curcumin prevented an excessive immune response, with control of cell damage, by decreasing the expression of P2X7 and A2A receptors, as well as its neuroprotective action, was increased against receptor activation purinergic A1. The ERK ½ signalling pathway, responsible for the production of inflammatory mediators and cell proliferation, was regulated by curcumin to attenuate pro-inflammatory responses and control cell proliferation. Together, these results show promise for the use of curcumin for the treatment of congenital toxoplasmosis.