Dopaminergic Receptors as Neuroimmune Mediators in Experimental Autoimmune Encephalomyelitis

Abstract

The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system with the pathogenesis of multiple sclerosis (MS). Herein, we investigate the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also examined if the treatment with pramipexole (PPX) -a dopamine D2/D3 receptor-preferring agonist -would be able to prevent the EAE-induced motor and mood dysfunction, as well as the underlying mechanisms of action. Our ndings showed that D2R immunocontent upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontent was signi cantly increased in the lymph nodes during the chronic phase of EAE. Also, during this phase, oxidative damage in the spinal cord and striatum of EAE animals was signi cantly higher. During the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. In addition, PPX treatment failed to inhibit EAE progression and anhedonic-like behavior. Otherwise, PPX inhibited the depressive-like behavior. Relevantly, PPX oral treatment downregulated IL-1β levels and increased BNDF content in the spinal cord after EAE induction. Altogether, it is possible to conclude that D2R participates in crosstalk between CNS and immune system during autoimmune and neuroin ammatory response induced by EAE, mainly in the acute and chronic phase of the disease. Relevantly, a dopamine D2/D3 receptor-preferring agonist mitigated depressive-like behavior induced by EAE, which offers a new possibility for treating depressive symptoms in MS patients.

Exploring the Role of Neurotransmitters in Multiple Sclerosis: An Expanded Review

“…In particular, pramipexole (PPX) (1 mg/kg), a D2/D3 receptor-preferring agonist, has been shown to reduce depressive-like behavior in EAE animal models. 90 Therefore, D2R might be implicated in the neuroinflammatory responses in EAE-related mood disorders. Another study has demonstrated that isosibiricin, a natural coumarin compound, could inhibit microglial activation by targeting D1/D2 receptor-dependent nucleotide binding domain like receptor protein 3 (NLRP3)/caspase-1 inflammasome pathway.…”

“…Given this evidence, dopaminergic receptors have been used as potential pharmaceutical targets in MS-related mood disorders. In particular, pramipexole (PPX) (1 mg/kg), a D2/D3 receptor-preferring agonist, has been shown to reduce depressive-like behavior in EAE animal models . Therefore, D2R might be implicated in the neuroinflammatory responses in EAE-related mood disorders.…”