Abstract
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, responsible for the onset of several long-term complications. Recent evidence suggests that cognitive dysfunction represents an emerging complication of DM, but the underlying molecular mechanisms are still obscure. Dopamine (DA), a neurotransmitter essentially known for its relevance in the regulation of behavior and movement, modulates cognitive function, too. Interestingly, alterations of the dopaminergic system have been observed in DM. This review aims to offer a comprehensive overview of the most relevant experimental results assessing DA’s role in cognitive function, highlighting the presence of dopaminergic dysfunction in DM and supporting a role for glucotoxicity in DM-associated dopaminergic dysfunction and cognitive impairment. Several studies confirm a role for DA in cognition both in animal models and in humans. Similarly, significant alterations of the dopaminergic system have been observed in animal models of experimental diabetes and in diabetic patients, too. Evidence is accumulating that advanced glycation end products (AGEs) and their precursor methylglyoxal (MGO) are associated with cognitive impairment and alterations of the dopaminergic system. Further research is needed to clarify the molecular mechanisms linking DM-associated dopaminergic dysfunction and cognitive impairment and to assess the deleterious impact of glucotoxicity.
Highlights
Introduction iationsDiabetes mellitus (DM) is a heterogeneous chronic metabolic disorder, characterized by hyperglycemia, representing a global epidemic public health problem [1]
DA is a neurotransmitter mainly synthesized in a two-step pathway in the cytosol of dopaminergic neurons, where the rate-limiting enzyme tyrosine hydroxylase (TH) hydroxylates L-tyrosine at the phenol ring, generating levodopa (L-DOPA)
Stern Y and coworkers in 1990 investigated general intellectual function, construction, language, memory, executive function, attention, and reaction time in MPTP-exposed individuals, characterized by reduced uptake of labeled 6-fluorodopa into the striatum. They featured significantly worse performances in a specific set of cognitive functions mediated by the dopaminergic system [109]
Summary
DA is a neurotransmitter mainly synthesized in a two-step pathway in the cytosol of dopaminergic neurons, where the rate-limiting enzyme tyrosine hydroxylase (TH) hydroxylates L-tyrosine at the phenol ring, generating levodopa (L-DOPA). DA receptors are coupled to guanosine triphosphate-binding proteins (G proteins), able to modulate second messenger levels and, in turn, specific signaling pathways [43]. D1 and D5 receptors are localized in postsynaptic neurons, are coupled to stimulatory G protein Gαs, and activate adenylyl cyclase, leading to cAMP production and PKA activation. PKA phosphorylates several different substrates, such as the two major subtypes of glutamate receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and N-Methyl-D-aspartate receptor), potassium, sodium [47], and calcium channels and specific transcription factors including CREB [48]. Its binding to phosphorylated D2 receptors leads to the formation of a complex including the serine threonine kinase Akt and the phosphatase PP2A, resulting in constitutive activation of Akt substrates GSK3 alpha and beta [52].
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