Tuesday, 26 January 2016

Dopamine modulation - a novel target for MS

Mol Neurobiol. 2016 Jan 22. [Epub ahead of print]


Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice.


Lieberknecht V, Junqueira SC, Cunha MP, Barbosa TA, de Souza LF, Coelho IS, Santos AR, Rodrigues AL, Dafré AL, Dutra RC.

Abstract

Experimental autoimmune encephalomyelitis (EAE) is the most used animal model of multiple sclerosis (MS) for the development of new therapies. Dopamine receptors can modulate EAE and MS development, thus highlighting the potential use of dopaminergic agonists in the treatment of MS, which has been poorly explored. Herein, we hypothesized that pramipexole (PPX), a dopamine D2/D3 receptor-preferring agonist commonly used to treat Parkinson's disease (PD), would be a suitable therapeutic drug for EAE. Thus, we report the effects and the underlying mechanisms of action of PPX in the prevention of EAE. PPX (0.1 and 1 mg/kg) was administered intraperitoneally (i.p.) from day 0 to 40 post-immunization (p.i.). Our results showed that PPX 1 mg/kg prevented EAE development, abolishing EAE signs by blocking neuroinflammatory response, demyelination, and astroglial activation in spinal cord. Moreover, PPX inhibited the production of inflammatory cytokines, such as IL-17, IL-1β, and TNF-α in peripheral lymphoid tissue. PPX was also able to restore basal levels of a number of EAE-induced effects in spinal cord and striatum, such as reactive oxygen species, glutathione peroxidase, parkin, and α-synuclein (α-syn). Thus, our findings highlight the usefulness of PPX in preventing EAE-induced motor symptoms, possibly by modulating immune cell responses, such as those found in MS and other T helper cell-mediated inflammatory diseases.

Pramipexole; prescription only.


Figure A: Pramipexole protected against EAE development; mean scores from naïve group, untreated EAE group, or animals treated with PPX (0.1 or 1mg/kg/day i.p.). B: Area under the curve of mean score.

Dysfunction in the dopaminergic system is well characterised in Parkinson's disease. What is its relevance in MS?

Immune cells express the rate limiting enzyme for dopamine synthesis (tyrosine hydroxylase), as well as dopaminergic receptors. D3 receptor activation in T cells, for instance changes the immune population composition, decreasing the Th17 and Th2, whilst increasing the Th1 pool and may influence T cell differentiation. Interferon-B, for instance induces production and release of dopamine from T lymphocytes. Whilst, bromocriptine, a D2R dopamine agonist has also been tried in rat EAE with similar findings (Dijkstra C et al. 1994, Therapeutic effect of the D2-dopamine agonist bromocriptine on acute and relapsing experimental allergic encephalomyelitis. Psychoneuroendocrinology 19: 135-142) and in two patients demonstrating paroxysmal improvement in symptoms, including intermittent numbness and tingling; although a placebo effect cannot be excluded (Khan O et al. 1995, Treatment of paroxysmal symptoms in multiple sclerosis with bromocriptine. JNNP 58:253). Further work has shown that D2 receptor activation diminishes T lymphocyte survival.

Pramipexole is D2/D3 receptor agonist and the EAE experiment demonstrates that if introduced at day 0 it diminishes the motor component of EAE in entirety (see figure). In further experiments, the authors demonstrate that Pramipexole reduces immune cell infiltration, demyelination and astroglial activation; attenuates pro-inflammatory cytokine production in lymph nodes; re-establishes oxidative damage and antioxidant defences to basal levels and restores Parkin and alpha-synuclein expression in the CNS (i.e. mitigate changes in the proteins related to PD).

There are a couple of notes of caution to consider: 1) Pramipexole and other dopamine derivatives play a major role in reward-motivation behaviours and have been linked to gambling, addiction to medication, and sexual behaviour; 2) the dose is important, majority of PD patients can tolerate 0.75mg-1mg three times a day - maximum dose is 4.5mg/day!; 3) the authors haven't tried the effects of the drug on a chronic relapsing EAE model which is more representative of MS. Bromocriptine, on the other hand has been tried in a chronic model and has been found not to affect the severity and duration of the first attack, but did reduce the duration of the subsequent attack.

4 comments:

  1. Cabergoline would have the same effect then?

    ReplyDelete
  2. Can this class of compounds help to treat relapses?

    ReplyDelete
    Replies
    1. Certainly not at the doses they used in these experiments.

      Delete

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