Pramipexole Stops MS in Animal Model – Helps Restless Legs, Fibromyalgia, and May Help Resistant Depression

In the mouse model of Multiple Sclerosis, Pramipexole, a antiparkinson drug, stops the brain neuroinflammation and that form of MS called “Experimental Autoimmune Encephalomyelitis”. This agent is used extensively for restless legs – Got MS and restless legs? – I would get on this drug…

The trade name for it is  Mirapex. Here is the MS abstract:

Mol Neurobiol. 2017 Mar;54(2):1033-1045. doi: 10.1007/s12035-016-9717-5. Epub 2016 Jan 22.
Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice.
Lieberknecht V1,2,3, Junqueira SC1,2, Cunha MP3, Barbosa TA1, de Souza LF3, Coelho IS2,4, Santos AR2,4, Rodrigues AL2,3, Dafré AL2,3, Dutra RC5,6.
Author information

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.

Also prameprazole anti-inflammatory effects could be useful in depression:

Neuropsychopharmacology (2017) 42, 363; doi:10.1038/npp.2016.217

Pramipexole in Treatment Resistant-Depression, Possible Role of Inflammatory Cytokines

Rodrigo Escalona1,2 and Jan Fawcett1

  1. 1Department of Psychiatry, University of New Mexico School of Medicine, Albuquerque, NM, USA
  2. 2New Mexico VA Health Care System, Albuquerque, NM, USA

Correspondence: Jan Fawcett, E-mail: jfawcett@salud.unm.edu

Anhedonia is one of the most important predictors to developing treatment-resistant depression. The ‘interest-activity’ symptom dimension that includes loss of interest, diminished activity, and inability to make decisions has been shown to predict poor outcome of antidepressant treatment in large prospective clinical studies (Uher et al, 2012). Anhedonia symptoms can be induced experimentally in animals and humans by inflammatory cytokines, including interferon-alpha. Cytokines can affect dopamine function in the basal ganglia. Associations between altered dopamine function and impaired cortical-striatal reward circuitry are found in patients with major depression who display increased peripheral inflammatory markers and cytokines that include IL-6, TNF-alpha, and CRP (Felger and Miller, 2012). Anhedonia is not unique to depression. As a trans-diagnostic psychopathological domain that appears in various psychiatric and medical conditions, anhedonia may receive pathogenic contributions from common cellular immunity mechanisms that affect reward systems (Swardfager et al, 2016). SSRIs and other first-line antidepressants fail to alleviate IFN—-induced anxiety and depressive symptoms. Traditional stimulants that increase dopamine release and methylphenidate that blocks its reuptake have minimal effects on fatigue and anhedonia in depressed patients with inflammation-associated medical conditions such as advanced cancer. These findings suggest potential roles for cellular inflammation in mediating the development of treatment resistance to traditional antidepressants and stimulants, specifically when fatigue and anhedonia persist. In Parkinson’s disease, where depression is common and anhedonia is a prominent feature, L-Dopa and other non-receptor specific dopamine agonists display little efficacy in preventing or treating depression. However, pramipexole, a relatively selective D3 dopamine agonist has shown to relieve depression in Parkinson’s disease. Also, in chronic and severe treatment-resistant depressed patients, including bipolar disorder, pramipexole at high doses has shown promising response (Fawcett et al, 2016). The selective expression of D3 receptors in the mesolimbic projection areas including the nucleus accumbens makes this dopamine receptor a promising target to overcome treatment-resistant depression where anhedonia symptoms may be perpetuated by inflammatory cytokines, such as in severe medical conditions with known increased levels of inflammation. The effects of pramipexole on brain immunological mechanisms are not fully understood. However, recent data suggest potentially important roles. Pramipexole attenuates the development of experimental autoimmune encephalomyelitis in mice, an animal model for multiple sclerosis (Lieberknecht et al, 2016). D3 receptors can be found in CD4-positive T cells, which are involved in the modulation of peripheral immune responses and promote neuro-inflammation in a murine model of Parkinson’s disease (Contreras et al, 2016). Future studies in treatment-resistant depression that use D3-preferring and other dopamine agonists should monitor inflammatory markers as well as specific measures of anhedonia to better understand the role of inflammation in anhedonia and treatment resistance.

It has been found to help the pain in Fibromyalgia:
Holman, Andrew J., and Robin R. Myers.
A randomized, double‐blind, placebo‐controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications.
Arthritis & Rheumatism 52.8 (2005): 2495-2505.
http://onlinelibrary.wiley.com/doi/10.1002/art.21191/full

“The mean ± SEM decrease in the VAS score for pain from baseline to the study end point was –2.48 ± 0.38 cm (36%) in the pramipexole group and –0.71 ± 0.54 cm (9.4%) in the placebo group.”

Their protocol was:  – going this way they had no issues with nausea or dizziness effects. -given at bedtime

  • 0.25 mg at week 1,
  • 0.5 mg at week 2,
  • 0.75 mg at week 3,
  • 1.0 mg at week 4,
  • 1.25 mg at week 5,
  • 1.5 mg at week 6,
  • 1.75 mg at week 7,
  • 2.0 mg at week 8,
  • 2.5 mg at week 9,
  • 3.0 mg at week 10,
  • 3.75 mg at week 11,
  • 4.5 mg at weeks 12, 13, and 14.

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It also works well in restless leg syndrome:

Restless legs syndrome improved by pramipexole

A double-blind randomized trial

Jacques Montplaisir, Alain Nicolas, Régine Denesle, Baltazar Gomez-Mancilla

Abstract

Background: Restless legs syndrome (RLS) is characterized by leg paresthesia associated with an irresistible urge to move. Currently used dopaminergic agents, such as levodopa, pergolide, and bromocriptine, offer incomplete control of sensory and motor symptoms and induce severe side effects.

Objective: To assess the safety and efficacy of pramipexole, a full D3-receptor agonist, in the treatment of RLS.

Methods: Ten RLS patients were studied before and after two 1-month treatments (placebo and pramipexole) administered in a double-blind crossover fashion. The severity of sensory and motor manifestations was assessed by 1 week of home questionnaires and 2 consecutive nights of sleep laboratory recordings. The indexes of periodic leg movement during sleep (PLMS) and during wakefulness (PLMW) were used as primary outcome variables.

Results: Pramipexole dramatically reduced the PLMS index to normal values (Wilcoxon, p = 0.005). The PLMW index was also significantly reduced (Wilcoxon, p = 0.007). Pramipexole also alleviated leg discomfort at bedtime and during the night as measured by the home questionnaires.

Conclusions: Pramipexole is the most potent therapeutic agent ever tested for RLS. Measures of both sensory and motor functions returned to normal values after treatment. Moreover, these results further support the hypothesis that D3 receptors play a major role in the physiopathology of this condition.

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Comment – Have an MS sufferer with pain, restless legs and depression that I started on Pramipexole 0.5mg hs as has a good stomach. Will increase as we go along. Have warned her about cases of people wanting to gamble on this drug…

Question is does one want to add another brain anti-inflammatory :

Statins recently shown to have anti inflammatory properties:

Neurochem Int. 2014 Jan;64:64-72. doi: 10.1016/j.neuint.2013.11.007. Epub 2013 Nov 22.
Ulinastatin attenuates experimental autoimmune encephalomyelitis by enhancing anti-inflammatory responses.
Feng M1, Shu Y2, Yang Y2, Zheng X3, Li R2, Wang Y2, Dai Y2, Qiu W2, Lu Z2, Hu X4.
Author information

Abstract
Multiple sclerosis (MS) is a common inflammatory and demyelinating neurological disease. Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, has been widely used to test MS treatment methods. Ulinastatin (UTI), a drug used to treat acute inflammatory disorders, has been tested in animal models of autoimmune inflammatory diseases, such as ulcerative colitis and crescentic glomerulonephritis. We recently found that UTI has a neuroprotective effect on EAE by reducing oligodendrocyte apoptosis and demyelination. The anti-inflammatory effects of UTI on EAE/MS, however, have never been investigated. We have therefore evaluated the anti-inflammatory effects of UTI in EAE and explored the mechanisms underlying this effect. EAE was induced in mice with and without UTI treatment. Inflammation and demyelination of spinal cords were evaluated by staining with hematoxylin and eosin and with Luxol fast blue, respectively. Inflammatory markers in serum were analyzed by the Luminex method, and spinal cords were evaluated by immunofluorescence and Western blotting. UTI significantly lowered the clinical and pathological scores and the serum concentrations of the inflammatory cytokines interleukin (IL)-1β, IL-6, and matrix metal protease-9 (MMP-9). UTI also reduced the expression of tumor necrosis factor-alpha (TNF-α)/nuclear factor kappaB (NF-κB)/inducible nitric oxide synthase (iNOS) proteins and decreased CD11b(+) cells in spinal cord lesions. UTI may protect against EAE in mice by suppressing inflammatory responses. We think that UTI might be a potential therapeutic agent for MS.

 

perhaps why simvastatin 80 mg helps reduce plaque by 40%

Interestingly, simvastatin showed early suggestion that it could help heal MS plaque (being so lipophylic gets into brain easily):
Vollmer, Timothy, et al.
Oral simvastatin treatment in relapsing-remitting multiple sclerosis.
The Lancet 363.9421 (2004): 1607-1608.
http://www.direct-ms.org/pdf/DrugsMS/Simvastatin%20Vollmer.pdf
They used 80 mg/day and got over 40% reduction in plaque MRI signals over 6 month.

Simvastatin has been found to inhibit certain inflammatory cytokines in MS:
Zhang, Xin, et al.
Simvastatin inhibits secretion of Th17‐polarizing cytokines and antigen presentation by DCs in patients with relapsing remitting multiple sclerosis.
European journal of immunology 43.1 (2013): 281-289.
http://onlinelibrary.wiley.com/doi/10.1002/eji.201242566/full

Atorvastatin also works in the animal model of MS:
Weber, Martin S., et al.
Neither T-helper type 2 nor Foxp3+ regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity.
Journal of neuroinflammation 11.1 (2014): 29.

However MS patients on Interferon DO NOT benefit from statins in several trials. Recent bottom line was that no conclusion can be made because of “conflicting results”:
Ciurleo, Rosella, Placido Bramanti, and Silvia Marino. “Role of statins in the treatment of multiple sclerosis.” Pharmacological Research (2014).
http://www.sciencedirect.com/science/article/pii/S1043661814000279

 

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