Caffeine Consumption Prevents Memory Impairment, Neuronal Damage, and Adenosine A2A Receptors Upregulation in the Hippocampus of a Rat Model of Sporadic Dementia

Abstract

Intracerebroventricular (icv) streptozotocin (STZ) administration induces pathological and behavioral alterations similar to those observed in Alzheimer's disease (AD) and is thus considered an experimental model of sporadic AD. Since caffeine (an adenosine receptor antagonist) and selective antagonists of adenosine A2A receptors modify the course of memory impairment in different amyloid-β-based experimental models of AD, we now tested the impact of caffeine on STZ-induced dementia and associated neurodegeneration in the hippocampus as well as on the expression and density of adenosine receptors. Adult male rats received a bilateral infusion of saline or STZ (3 mg/kg, icv), which triggered memory deficits after four weeks, as gauged by impaired object recognition memory. This was accompanied by a reduced NeuN immunoreactivity in the hippocampal CA1 region and an increased expression and density of adenosine A2A receptors (A2AR), but not A1R, in the hippocampus. Caffeine consumption (1 g/L in the drinking water starting 2 weeks before the STZ challenge) prevented the STZ-induced memory impairment and neurodegeneration as well as the upregulation of A2AR. These findings provide the first demonstration that caffeine prevents sporadic dementia and implicate the control of central A2AR as its likely mechanism of action.

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

“…This ability of A 2A R KO to prevent A53T α-Syn-induced working memory impairment is consistent with the previous finding that A 2A R blockade prevents memory dysfunction caused by Aβ peptides via p38 MAPK pathway (Canas et al, 2009b;Dall'Igna et al, 2007) and transgenic hAPP AD model (Orr et al, 2015), by R6/2 transgenic model of HD (Li et al, 2015b), by the PD model with focal dopamine depletion in cortex (Kadowaki Horita et al, 2013), and by sporadic dementia (Espinosa et al, 2013). The demonstration of the hippocampal A 2A R up-regulation by A53T α-Syn fibrils and the reversal of α-Syn-induced cognitive impairments suggest a novel molecular mechanism linking α-Syn aggregates to cognitive impairments via the up-regulated A 2A R (in the absence or presence of neurodegeneration).…”

Chronic nicotine attenuates behavioral and synaptic plasticity impairments in a streptozotocin model of Alzheimer’s disease

“…Shoham et al (2007) and Espinosa et al (2013) have reported recognition memory impairments in icv-STZ-treated rats, and a comparative study between rodent models of sAD (Chen et al, 2013) has shown that the icv-STZ model is even more detrimental to short-term memory than the transgenic 3xTg-AD mouse model. In line with the icv-STZ impact on cognition, spatial discrimination impairments in STZtreated animals were shown to correlate with reduced choline acetyltransferase (ChAT) activity in the hippocampus (Blokland and Jolles, 1993;Prickaerts et al, 1999).…”

Therapeutic Opportunities for Caffeine and A_2A Receptor Antagonists in Retinal Diseases

“…Sporadic dementia is prevented by caffeine administration [26] and the lowest risk of dementia or AD was found among coffee drinkers of 3-5 cups per day at midlife [27], which was attributed to the antioxidant properties of caffeine [28]. The administration of caffeine also prevents the loss of dopaminergic neurons in the substantia nigra [29], which is a feature of PD [30].…”