Evaluation of Urea-Based Inhibitors of the Dopamine Transporter Using the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis

Abstract

The dopaminergic system is involved in the regulation of immune responses in various homeostatic and disease conditions. For conditions such as Parkinson’s disease and multiple sclerosis (MS), pharmacological modulation of dopamine (DA) system activity is thought to have therapeutic relevance, providing the basis for using dopaminergic agents as a treatment of relevant states. In particular, it was proposed that restoration of DA levels may inhibit neuroinflammation. We have recently reported a new class of dopamine transporter (DAT) inhibitors with high selectivity to the DAT over other G-protein coupled receptors tested. Here, we continue their evaluation as monoamine transporter inhibitors. Furthermore, we show that the urea-like DAT inhibitor (compound 5) has statistically significant anti-inflammatory effects and attenuates motor deficits and pain behaviors in the experimental autoimmune encephalomyelitis model mimicking clinical signs of MS. To the best of our knowledge, this is the first study reporting the beneficial effects of DAT inhibitor-based treatment in animals with induced autoimmune encephalomyelitis, and the observed results provide additional support to the model of DA-related neuroinflammation.

Chemogenetic Manipulation of Amygdala Kappa Opioid Receptor Neurons Modulates Amygdala Neuronal Activity and Neuropathic Pain Behaviors

“…Ultrasonic vocalizations were used to assess the emotional-affective responses to noxious stimuli in different experimental pain conditions [36][37][38][39][40]. Ultrasonic (25 ± 4 kHz) vocalizations were measured using a bat detector that was connected to a filter and amplifier (UltraVox four-channel system; Noldus Information Technology, Leesburg, VA, USA) as described in our previous work [41]. Animals were briefly anesthetized with isoflurane (2% precision vaporizer) to allow for gentle and slightly restrained placement in a custom-designed recording chamber that permitted hindlimb access for mechanical test stimuli.…”

“…Animals were briefly anesthetized with isoflurane (2% precision vaporizer) to allow for gentle and slightly restrained placement in a custom-designed recording chamber that permitted hindlimb access for mechanical test stimuli. After habituation to the chamber, brief (15 s) innocuous (100 g/6 mm 2 ) or noxious (300 g/6 mm 2 ) mechanical stimuli were applied to the hind paw as described before [41], using a calibrated forceps with a force transducer to monitor the applied force (in grams). The duration of ultrasonic vocalizations was analyzed in each mouse for 1 min after the onset of the mechanical stimulus using Ultravox 2.0 software (Noldus Information Technology, Leesburg, VA, USA).…”

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

“…Urea-like suppressors of DAT have also been studied in EAE. Urea-like DAT suppressors produced an anti-inflammatory effect in MS, 86 suggesting that DAT-suppressing agents can be an effective treatment for EAE. Dopamine can promote the glucocortoid-resistant interleukin-17 (IL-17)-producing T cells (Th17) phenotype in MS. 87 One potential underlying mechanism may be the ability of CD4+ T cells (1 × 10 6 mL −1 ) to trigger IL-6 production.…”

Effects of Nicotine Exposure From Tobacco Products and Electronic Cigarettes on the Pathogenesis of Neurological Diseases: Impact on CNS Drug Delivery

“…Furthermore, macrophages of the brain secrete chemical signals that upregulate the secretion of cytokines such as TNF-α, IL-1β, and IL-6 (Contreras et al, 2016). These cytokines, along with neurotrophic factors such as brain-derived neurotrophic factor, nerve growth factor, and vascular endothelial growth factor, all exacerbate the state of chronic inflammation in the CNS (Ashraf- Uz-Zaman et al, 2022). Since MS has been correlated with an impaired immune system, it can be assumed that the pathology of the disease is attributed to genetic and environmental factors (Mitrovic et al, 1995).…”