Acamprosate modulates experimental autoimmune encephalomyelitis

Sternberg, Zohara; Cesario, A.; Rittenhouse-Olson, Kate; Sobel, Raymond A.; Pankewycz, O.; Whitcomb, Tiffany; Sternberg, Daniel; Munschauer, F

doi:10.1007/s10787-011-0097-1

Cited by 9 publications

(7 citation statements)

References 44 publications

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“…The present piece of work suggests that homotaurine supplementation in aMCI individuals carrying APOE ε4 has a positive consequence on episodic memory loss due, at least in part, to homotaurine anti-inflammatory effects targeting IL-18. While some studies highlighted the potential of homotaurine and its derivatives to benefit patients with MCI (Martorana et al, 2014 ; Spalletta et al, 2016 ), and to modulate inflammation in mouse models (Sternberg et al, 2012 ), this is the first evidence ever provided that homotaurine supplementation holds anti-inflammatory properties associated with memory improvement in patients with cognitive impairment.…”

Section: Discussionmentioning

confidence: 98%

Anti-inflammatory Effects of Homotaurine in Patients With Amnestic Mild Cognitive Impairment

Bossù

Salani

Ciaramella

et al. 2018

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a fatal dementing neurodegenerative disease, currently lacking an efficacious disease-modifying therapy. In the last years, there has been some interest in the use of homotaurine as a potential therapeutic compound for AD, but more work is still needed to prove its efficacy as disease modifier in dementia. Since inflammation is believed to play a key role in AD development, we sought to investigate here the in vivo homotaurine effect on inflammatory response in patients at the earliest stages of AD, i.e., suffering from amnestic mild cognitive impairment (aMCI). Thus, the present study aims to evaluate the effects of homotaurine supplementation on cytokine serum levels and memory performances in MCI patients. Neuropsychological, clinical and cytokine assessment was performed at baseline (T0) and after 1 year (T12) of homotaurine supplementation in 20 patients categorized as carriers (n = 9) or no carriers (n = 11) of the ε4 allele of the apolipoprotein E (APOE) gene, the strongest genetic risk factor for AD. The serum levels of the pro-inflammatory mediators Interleukin (IL) 1β, Tumor necrosis factor-alpha (TNFα), IL-6 and IL-18, contextually with the anti-inflammatory molecules IL-18 binding protein (IL-18BP) and Transforming growth factor-beta (TGFβ), were analyzed to explore significant differences in the inflammatory status between T0 and T12 in the two APOE variant carrier groups. No significant differences over time were observed in patients as for most cytokines, except for IL-18. Following homotaurine supplementation, patients carrying the APOEε4 allele showed a significant decrease in IL-18 (both in its total and IL-18BP unbound forms), in turn associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI may have a positive consequence on episodic memory loss due, at least in part, to homotaurine anti-inflammatory effects. This study strongly suggests that future research should focus on exploring the mechanisms by which homotaurine controls brain inflammation during AD progression.

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Section: Discussionmentioning

confidence: 98%

Anti-inflammatory Effects of Homotaurine in Patients With Amnestic Mild Cognitive Impairment

Bossù

Salani

Ciaramella

et al. 2018

Front. Aging Neurosci.

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“…Mice were subjected to 30 minutes of transient focal cerebral ischemia as described below followed by intraperitoneal treatment with either acamprosate (Sigmal-Aldrich, Taufkirchen, Germany; solved in NaCl) or standard saline (control) during reperfusion, at 3, 6, 9, 12, and 24 hours after stroke. Referring to previous studies, [15][16][17][18][19][20] mice received a modified injection protocol with a single intraperitoneal injection of acamprosate at a dose of 400 mg/kg bodyweight (BW). To exclude toxic side effects of acamprosate after high dosage bolus application, analysis of potential weight loss and blood count analysis was performed 1 day before stroke induction as well as on days 7 and 14 after stroke ( Table 1).…”

Section: Experimental Paradigmmentioning

confidence: 99%

“…[12][13][14] In addition to the aforementioned effects during alcohol dependence, experimental evidence suggests a therapeutic role for acamprosate in neurologic disorders such as multiple sclerosis. 15 Since activation of the glutamatergic system and stimulation of NMDAR are decisive in the development of cerebral ischemia as stated afore, a single study analyzed the therapeutic potential of acamprosate in a rat model of cerebral ischemia. 16 Although limited and descriptive in its nature, this study remained the only one demonstrating neurologic recovery on day 3 after stroke after pretreatment with acamprosate.…”

Section: Introductionmentioning

confidence: 99%

The Indirect NMDAR Antagonist Acamprosate Induces Postischemic Neurologic Recovery Associated with Sustained Neuroprotection and Neuroregeneration

Doeppner

Pehlke

Kaltwasser

et al. 2015

J Cereb Blood Flow Metab

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Cerebral ischemia stimulates N-methyl-D-aspartate receptors (NMDARs) resulting in increased calcium concentration and excitotoxicity. Yet, deactivation of NMDAR failed in clinical studies due to poor preclinical study designs or toxicity of NMDAR antagonists. Acamprosate is an indirect NMDAR antagonist used for patients with chronic alcohol dependence. We herein analyzed the therapeutic potential of acamprosate on brain injury, neurologic recovery and their underlying mechanisms. Mice were exposed to cerebral ischemia, treated with intraperitoneal injections of acamprosate or saline (controls), and allowed to survive until 3 months. Acamprosate yielded sustained neuroprotection and increased neurologic recovery when given no later than 12 hours after stroke. The latter was associated with increased postischemic angioneurogenesis, albeit acamprosate did not stimulate angioneurogenesis itself. Rather, increased angioneurogenesis was due to inhibition of calpain-mediated pro-injurious signaling cascades. As such, acamprosate-mediated reduction of calpain activity resulted in decreased degradation of p35, increased abundance of the pro-survival factor STAT6, and reduced N-terminal-Jun-kinase activation. Inhibition of calpain was associated with enhanced stability of the blood-brain barrier, reduction of oxidative stress and cerebral leukocyte infiltration. Taken into account its excellent tolerability, its sustained effects on neurologic recovery, brain tissue survival, and neural remodeling, acamprosate is an intriguing candidate for adjuvant future stroke treatment.

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“…Topiramate, however, primarily affects other ion channels (e.g., sodium and calcium channels) and enzymes 22 , 23 and vigabatrin does not bind to GABA-Rs but rather inhibits GABA transaminase 23 , and both drugs have multiple adverse effects. Other studies have shown that the anti-alcohol dependence drug acamprosate, which has structural similarities with GABA, can limit EAE 24 , but recent studies indicate that acamprosate does not act directly through GABA A -Rs 25 , 26 . Benzodiazepines and barbiturates are BBB-permeable GABA A -R positive allosteric modulators that can potentiate the opening of GABA A -R chloride channels, but only after a GABA A -R agonist opens the channel, and these drugs can be addictive.…”

Section: Introductionmentioning

confidence: 97%

Homotaurine, a safe blood-brain barrier permeable GABAA-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis

Tian

Dang

Wallner

et al. 2018

Sci Rep

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There is a need for treatments that can safely promote regulatory lymphocyte responses. T cells express GABA receptors (GABAA-Rs) and GABA administration can inhibit Th1-mediated processes such as type 1 diabetes and rheumatoid arthritis in mouse models. Whether GABAA-R agonists can also inhibit Th17-driven processes such as experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is an open question. GABA does not pass through the blood-brain barrier (BBB) making it ill-suited to inhibit the spreading of autoreactivity within the CNS. Homotaurine is a BBB-permeable amino acid that antagonizes amyloid fibril formation and was found to be safe but ineffective in long-term Alzheimer’s disease clinical trials. Homotaurine also acts as GABAA-R agonist with better pharmacokinetics than that of GABA. Working with both monophasic and relapsing-remitting mouse models of EAE, we show that oral administration of homotaurine can (1) enhance CD8+CD122+PD-1+ and CD4+Foxp3+ Treg, but not Breg, responses, (2) inhibit autoreactive Th17 and Th1 responses, and (3) effectively ameliorate ongoing disease. These observations demonstrate the potential of BBB-permeable GABAA-R agonists as a new class of treatment to enhance CD8+ and CD4+ Treg responses and limit Th17 and Th1-medaited inflammation in the CNS.

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Acamprosate modulates experimental autoimmune encephalomyelitis

Abstract: Acamprosate and other taurine analogs have a potential for future MS therapy.

Cited by 9 publications

References 44 publications

Anti-inflammatory Effects of Homotaurine in Patients With Amnestic Mild Cognitive Impairment

Anti-inflammatory Effects of Homotaurine in Patients With Amnestic Mild Cognitive Impairment

The Indirect NMDAR Antagonist Acamprosate Induces Postischemic Neurologic Recovery Associated with Sustained Neuroprotection and Neuroregeneration

Homotaurine, a safe blood-brain barrier permeable GABAA-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis

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