Theobromine-Induced Changes in A1 Purinergic Receptor Gene Expression and Distribution in a Rat Brain Alzheimer’s Disease Model

Abstract

Dementia caused by Alzheimer's disease (AD) is mainly characterized by accumulation in the brain of extra- and intraneuronal amyloid-β (Aβ) and tau proteins, respectively, which selectively affect specific regions, particularly the neocortex and the hippocampus. Sporadic AD is mainly caused by an increase in apolipoprotein E, a component of chylomicrons, which are cholesterol transporters in the brain. Recent studies have shown that high lipid levels, especially cholesterol, are linked to AD. Adenosine is an atypical neurotransmitter that regulates a wide range of physiological functions by activating four P1 receptors (A1, A2A, A2B, and A3) and P2 purinergic receptors that are G protein-coupled. A1 receptors are involved in the inhibition of neurotransmitter release, which could be related to AD. The aim of the present work was to study the effects of a lard-enriched diet (LED) on cognitive and memory processes in adult rats (6 months of age) as well as the effect of theobromine on these processes. The results indicated that the fat-enriched diet resulted in a long-term deterioration in cognitive and memory functions. Increased levels of Aβ protein and IL-1β were also observed in the rats fed with a high-cholesterol diet, which were used to validate the AD animal model. In addition, the results of qPCR and immunohistochemistry indicated a decrease in gene expression and distribution of A1 purinegic receptor, respectively, in the hippocampus of LED-fed rats. Interestingly, theobromine, at both concentrations tested, restored A1 receptor levels and improved cognitive functions and Aβ levels for a dose of 30 mg/L drinking water.

Tumor Necrosis Factor-Alpha Alters Electrophysiological Properties of Rabbit Hippocampal Neurons

“…Dietary cholesterol has been widely recognized as one of the best approaches to modeling sporadic AD in rabbits [1, 4, 35], rats [57–59], mice [48, 60], and guinea pigs [61]. Previous studies show that high cholesterol diet can increase TNF-α expression in mice [48, 49] and rats [62], our data revealed dietary cholesterol concentrations increased TNF-α expression in the rabbit hippocampus, suggesting dietary cholesterol can model a persistent TNF-α elevation in hippocampus.…”

Alzheimer and Purinergic Signaling: Just a Matter of Inflammation?

“…In addition, its effect on the increase in soluble Aβ has been detected, suggesting a protective role for A 1 agonists [41]. On the other hand, it has been reported that a fat-enriched diet induced cognitive and memory dysfunctions as well as a reduction in the A 1 hippocampal receptors that were reverted by the A 1 receptor's antagonist, theobromine [42].…”

Methylxanthines and Neurodegenerative Diseases: An Update

“…Moreover, theobromine showed prophylactic neuroprotection against damage to cognitive functions and levels of Aβ when 30 mg/L were added to drinking water. The authors suggest that the reducing Aβ effect could be mediated by the antioxidant and anti-inflammatory capacities of theobromine via decreased SOD1 and NFκB levels [49]. Moreover, theobromine isonucleotide analogs were synthesized and evaluated as active compounds in the inhibition of cholinesterases, since their low cytotoxicity makes them interesting as therapeutic molecules for AD [50].…”