Diabetes mellitus (DM) is a metabolic disorder characterized by high blood glucose levels (hyperglycemia), which results from inadequate regulation of the homeostasis of carbohydrate, lipid, and protein metabolism by the hormone insulin [1]. Thus, the lack of this hormone, caused by the autoimmune destruction of pancreatic β cells, is the main characteristic of type 1 diabetes mellitus (T1DM) [2,3].

Hyperglycemia leads to changes that develop more insidiously in the structure and physiology of the brain, especially in the hippocampus region, which is known to be involved in the formation, organization, and storage of memories [5,6]. Thus, these changes represent a complication of diabetes, which is called Diabetic Encephalopathy [6,7].

Diabetic Encephalopathy (DE) encompasses structural and functional impairment of the central nervous szstem (CNS). Cognitive dysfunction, changes in brain signal conduction, neurotransmission, synaptic plasticity, and motor impairment are characteristics of this complication [8,9]. These features are associated with aberrant synaptogenesis and neuroinflammation in the hippocampus, leading to cognitive decline [7].

Previous studies have demonstrated a strong association between diabetes, neurodegeneration, cognitive impairment, and dementia [8,10,11,12]. Thus, those affected by this metabolic syndrome may present deficits in specific cognitive functions such as processing speed, attention, executive function, and semantic memory [13,14]. In this context, the cholinergic system is noteworthy, having a key role in several vital functions, such as behavior, learning, memory, control of cerebral blood flow, and inflammation [15,16,17].

In addition to the cholinergic system, the purinergic signaling pathway plays a relevant neurological role, by modulating the functioning of various types of CNS cells (neurons, microglia, etc.) [18]. The purine nucleotides (ATP, ADP, AMP) and the main degradation nucleoside adenosine (Ado), exert their role by binding to purinergic receptors. These receptors are divided into P1 receptors, activated by Ado, and P2 receptors activated by ATP and/or ADP, mainly. P2 receptors have two subfamilies, ionotropic P2X receptors and metabotropic P2Y receptors [19,20]. Thus, the concentration of extracellular nucleotides and nucleoside is modulated by the activity of an enzymatic chain beginning with the action of E-NTPDase (Ecto-nucleoside triphosphate diphosphohydrolase, EC 3.6.1.5), which catalyzes the hydrolysis of ATP and/or ADP into AMP, then E-NPP (Ecto-nucleotide pyrophosphatase/phosphodiesterase), which hydrolyzes ATP to AMP, then the enzyme E-5′-nucleotidase (E-5′-NT, EC 3.1.3.5) which hydrolyzes the AMP molecule to Ado, which is finally degraded by adenosine deaminase (ADA, EC 3.5.4.4) generating inosine [21,22,23,24].

Related to this, ATP, when in high extracellular concentrations during purinergic signaling, acts as a pro-inflammatory agent participating in the activation of inflammasomes and leading to the release of interleukin 1β (IL-1β) through caspase activation [22,25]. In addition, the nucleoside Ado, a product of the hydrolysis of ATP or ADP, has been highlighted for its importance in the brain [26]. This nucleoside mediates the inhibition of important phenomena in the formation of long-term memory (long-term potentiation (LTP)) and synaptic plasticity, by binding to A1R-type receptors (inhibitory) located in the areas of the brain most involved in cognition such as the hippocampus and cortex. Furthermore, activation of this receptor (A1R) is also associated with neuromodulation and neuroprotection [27,28,29,30]. On the other hand, neuroinflammation is reported to be involved in the development of DE. Thus, diabetic animals have high gene expression of pro-inflammatory cytokines in the hippocampus, a brain region critical for cognition [31].

In contrast, the activation of A2R receptors (facilitators), mediated by Ado, is involved in neurodegeneration and neuroinflammation processes, both related to memory impairment. In particular, A2AR activation has been associated with behavioral responses such as hypolocomotion and decreased working memory [29]. However, in cases of neurodegenerative diseases, activation of this receptor may provide neuroprotection [29,30,32]. Additionally, Ado may interfere with the receptors of other neuromodulators [28], and may also mediate the immunosuppressive and anti-inflammatory response, inhibiting the production of pro-inflammatory cytokines [24,33].

Currently, there are many available medications to treat diabetes, however, none of them are specific to prevent or improve cognitive dysfunction in DE [1,34]. In this context, several preventive and treatment strategies focused on natural compounds have been investigated. Thus, phenolic compounds such as caffeic acid (CA), which is found in coffee, wine, tea, apples, grapes, and tomatoes, among other vegetables and fruits [35,36,37], seems to contribute positively by acting through different mechanisms. This phenolic acid is known to exert functions such as antioxidant [38], anti-inflammatory [36,39,40], neuroprotective [41,42], immunomodulatory [43], and antineoplasic [44,45].

Considering the already known therapeutic effects of CA, this study aimed to evaluate the effect of CA treatment on the neuromodulation of purinergic and cholinergic receptors and enzymes and inflammatory parameters in a model of STZ-induced type 1 diabetes mellitus (T1DM) in rats.