Efeito protetor de nanocápsulas poliméricas contendo crisina em modelo de doença de Alzheimer induzida por injeção intracerebroventricular do peptídeo β-amilóide 1-42

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized clinically by progressive loss of cognitive function, neuropsychiatric and behavioral disorders. Pathologically the disease is characterized by abnormal accumulation of β-amyloid peptide (Aß) in cortex and hippocampus, intracellular neurofibrillary tangles consisting of hyperphosphorylated Tau, and synaptic dysfunction progressively later neuronal loss. The therapeutic options available improve symptoms but did not prevent disease progression, therefore, is still missing an effective therapeutic strategy for AD. Chrysin (5, 7-dihidroxiflavone) is a flavonoid found in natural plant extracts (such as Passiflora caerulea and Populus tremula), honey and propolis which has significant pharmacological properties including antioxidant, anti-inflammatory, hypolipidemic, anti-atherogenic, anti-cancer effects and, more significantly, neuroprotection. However, there are some disadvantages that may limit their potential application in therapeutics such as low solubility and intestinal malabsorption. Adding to this, a key fact in Neurotherapy is the restrictive effect of the blood-brain barrier (BBB), which limits the effectiveness of treatments. Many studies have focused on this fundamental problem by designing different strategies to facilitate the transition of assets across the BBB. Among these, nanotechnology-based approaches have gained significant momentum as they can effectively carry active substances through the BBB. The 7 objective of this work was to prepare a system based on nanoparticles, capable of relaying chrysin, as well as investigating the biological effects in a model of AD induced by intracerebroventricular injection (icv) of Beta amyloid1-42 peptide (Aβ1-42) in swiss mice females aged between 18 and 22 months. Therefore, it was determined parameters of oxidative stress, neuroinflammation and levels of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex and hippocampus, it was also observed cognitive behavioral effects in mice. The animals were divided into 10 groups: (1) vehicle/phosphate-buffered saline (PBS); (2) Vehicle/blank-nanocapsule (NC); (3) vehicle/free chrysin (5 mg / kg); (4) Vehicle/NC-chrysin (1 mg / kg); (5) vehicle/NC-chrysin (5 mg / kg); (6) Aβ1-42/PBS; (7) Aβ1-42/blank-NC; (8) Aβ1-42/free chrysin (5 mg / kg); (9) Aβ1-42/NC-chrysin (1mg / kg) and; (10) Aβ1-42/NC-chrysin (5 mg / kg). The Aβ1-42 peptide or vehicle were infused icv injection and, one day later, treatment began, orally, for 14 days. After the end of treatment, animals were subjected to behavioral testing. The results showed that the neuroprotective effects of chrysin were higher when administered in nanoparticles. The nano system improved chrysin concentrations in the brain tissue as well as the pharmacological effectiveness. The present study demonstrated that treatment with chrysin, especially in nanoparticle formulation was effective in attenuating the following shortcomings arising from exposure of mice to Aβ1-42: the memory impairment in behavioral tests; the increased reactive oxygen species (RS), tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) levels, reduction non-thiol protein (NPSH), BDNF, and IL-10 levels; increasing the glutathione peroxidase (GPx) and glutathione reductase (GR) activity in the prefrontal cortex and hippocampus. In conclusion, these results demonstrate that blocking neuroinflammation and oxidative stress is involved in the neuroprotective effect of chrysin in this model, moreover, suggest that the nanoparticle formulation potentiates their effects, which may provide a new therapeutic approach for the treatment and prevention of AD.