Taurine Abstracts 9

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Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study).
            (Aisen et al., 2011) Download
INTRODUCTION:  The aim of the study was to assess the clinical efficacy, safety, and disease-modification effects of tramiprosate (homotaurine, ALZHEMED(TM)) in mild-to-moderate Alzheimer's disease (AD). MATERIAL AND METHODS:  Double-blind, placebo-controlled, randomized trial in 67 clinical centres across North America. Patients aged ≥ 50 years, with mild-to-moderate AD (Mini-Mental State Examination score between 16 and 26) and on stable doses of cholinesterase inhibitors, alone or with memantine. INTERVENTION:  78-week treatment with placebo, tramiprosate 100 mg or tramiprosate 150 mg BID. MEASUREMENTS:  Alzheimer Disease Assessment Scale - cognitive subscale (ADAS-cog) and Clinical Dementia Rating - Sum of Boxes (CDR-SB) assessments were performed at baseline and every 13 weeks. Baseline and 78-week magnetic resonance imaging (MRI) hippocampus volume (HV) measurements were conducted in a subgroup of patients. RESULTS:  A total of 1,052 patients were enrolled and 790 (75.1%) completed the 78-week trial. Patient discontinuation and reasons for withdrawal were similar across groups. Planned analyses did not reveal statistically significant between-group differences. Lack of adequate statistical validity of the planned analysis models led to the development of revised predictive models. These adjusted models showed a trend toward a treatment effect for ADAS-cog (P = 0.098) and indicated significantly less HV loss for tramiprosate 100 mg (P = 0.035) and 150 mg (P = 0.009) compared to placebo. The incidence of adverse events was similar across treatment groups. CONCLUSIONS:  The primary planned analyses did not show a significant treatment effect, but were confounded by unexplained variance. Post-hoc analyses showed a significant treatment-related reduction in HV loss. However, there was only a trend towards slowing of decline on the ADAS-cog and no slowing of decline on the CDR-SB. These results must be interpreted in consideration of the limitations of clinical and disease-modification outcome measures and their relationship, the heterogeneity of the disease and the impact of confounding demographic and clinical variables.


 

Homotaurine induces measurable changes of short latency afferent inhibition in a group of mild cognitive impairment individuals.
            (Martorana et al., 2014) Download
Current treatment options for patients with Alzheimer's disease (AD) are limited at providing symptomatic relief, with no effects on the underlying pathophysiology. Recently, advances in the understanding of the AD pathogenesis highlighted the role of ABeta (Aβ) oligomers particularly interfering with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD). These findings led to the development of potential anti-amyloid therapies, and among them homotaurine, a glycosaminoglycan mimetic designed to interfere with the actions of Aβ early in the cascade of amyloidogenic events, and by its γ-aminobutyric acid type (GABA) A receptor affinity. Recently, we showed that AD patients have impaired LTP-like cortical plasticity, as measured by standard theta burst stimulation protocols applied over the primary motor cortex (M1). Furthermore, AD patients have a weakened short latency afferent inhibition (SLAI), a neurophysiological measure of central cholinergic transmission, which changes reflect the cholinergic dysfunction occurring in the pathology. Here, we aimed at investigating whether homotaurine administration could modulate in vivo measured mechanisms of synaptic plasticity, namely LTP and LTD, and also SLAI in a group of mild cognitive impaired patients. We observed that homotaurine administration did not induce relevant changes of both LTP and LTD recordings, while induced changes of SLAI in our group of patients. We suggest that homotaurine effects are dependent on changes of cortical GABA transmission suggesting a potential role for this compound in ameliorating the cholinergic transmission by modulating the inhibitory cortical activity.

Homotaurine in Parkinson's disease.
            (Ricciardi et al., 2015) Download
Homotaurine is a natural compound of red algae, which has been demonstrated to have a neuroprotective effect and has been evaluated as a possible therapeutic agent for Alzheimer's disease. This was a single blind, randomized, controlled study to evaluate the safety and efficacy of homotaurine in patients with Parkinson's disease (PD) and cognitive impairment. Patients were evaluated at baseline and 6 months later. Assessments included, the evaluation of: motor and non-motor conditions and complications (Unified Parkinson's Disease Rating Scale, UPDRS); disability and quality of life; depression; excessive daytime sleepiness and fatigue. An extensive neuropsychological tests battery was administered evaluating specific cognitive domains: memory, phonemic verbal fluency, executive functions and selective visual attention. After baseline testing, patients were allocated to one of the two groups: (A) treatment group: patients treated with homotaurine 100 mg; (B) control group: patients not treated with homotaurine. Forty-seven patients were evaluated at baseline, 24 (51 %) completed the study (PD-homotaurine: n = 11; 44 % and PD-controls: n = 13; 59 %); discontinuation rate was similar across subjects (p = 1.0). Intention to treat analyses to evaluate homotaurine safety showed mild side effects (gastrointestinal upsetting) in 3 patients. Per protocol analyses of homotaurine efficacy showed no difference between groups. Within group analyses showed that PD-homotaurine patients had better score at UPDRS-I at the end of the study compared to baseline (p = 0.017) and at Epworth Sleepiness Scale (p = 0.01). No other differences were found. No significant difference arose for the PD-ctrl group. Homotaurine is a safe drug. Our data suggest a beneficial effect of homotaurine on excessive sleepiness. Future studies are encouraged to confirm this promising role of homotaurine in promoting the sleep/awake cycle in patients with PD.

Intravitreal injection of forskolin, homotaurine, and L-carnosine affords neuroprotection to retinal ganglion cells following retinal ischemic injury.
            (Russo et al., 2015) Download
PURPOSE:  Retinal ganglion cell (RGC) death is the final event leading to visual impairment in glaucoma; therefore, identification of neuroprotective strategies able to slow down or prevent the process is one of the main challenges for glaucoma research. The purpose of this study was to evaluate the neuroprotective potential of RGC death induced by the in vivo transient increase in intraocular pressure (IOP) of a combined treatment with forskolin, homotaurine, and L-carnosine. Forskolin (7beta-acetoxy-8, 13-epoxy-1a, 6β, 9a-trihydroxy-labd-14-en-11-one) is an activator of adenylate cyclase that decreases IOP by reducing aqueous humor production and functions as a neuroprotector due to its neurotrophin-stimulating activity. Homotaurine is a natural aminosulfonate compound endowed with neuromodulatory effects, while the dipeptide L-carnosine is known for its antioxidant properties. METHODS:  Retinal ischemia was induced in the right eye of adult male Wistar rats by acutely increasing the IOP. Forskolin, homotaurine, and L-carnosine were intravitreally injected and RGC survival evaluated following retrograde labeling with FluoroGold. Total and phosphorylated Akt and glycogen synthase kinase-3β (GSK-3β) protein levels, as well as calpain activity, were analyzed with western blot. Protein kinase A (PKA) was inhibited by intravitreal injection of H89. RESULTS:  A synergic neuroprotective effect on RGC survival was observed following the combined treatment with forskolin, homotaurine, and L-carnosine compared to forskolin alone. The observed neuroprotection was associated with reduced calpain activity, upregulation of phosphoinositide 3-kinase (PI3K)/Akt pathway, and inhibition of GSK-3β but was independent from PKA activation and distinct from the hypotensive effects of forskolin. CONCLUSIONS:  A multidrug/multitarget approach, by interfering with several pathways involved in RGC degeneration, may be promising to achieve glaucoma neuroprotection.


 

Homotaurine Effects on Hippocampal Volume Loss and Episodic Memory in Amnestic Mild Cognitive Impairment.
            (Spalletta et al., 2016) Download
Homotaurine supplementation may have a positive effect on early Alzheimer's disease. Here, we investigated its potential neuroprotective effect on the hippocampus structure and episodic memory performances in amnestic mild cognitive impairment (aMCI). Neuropsychological, clinical, and neuroimaging assessment in 11 treated and 22 untreated patients were performed at baseline and after 1 year. Magnetic resonance data were analyzed using voxel-based morphometry to explore significant differences (Family Wise Error corrected) between the two groups over time. Patients treated with homotaurine showed decreased volume loss in the left and right hippocampal tail, left and right fusiform gyrus, and right inferior temporal cortex which was 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 has a positive effect on hippocampus atrophy and episodic memory loss. Future studies should further clarify the mechanisms of its effects on brain morphometry.

 


References

Aisen, PS, et al. (2011), ‘Tramiprosate in mild-to-moderate Alzheimer’s disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study).’, Arch Med Sci, 7 (1), 102-11. PubMed: 22291741
Martorana, A, et al. (2014), ‘Homotaurine induces measurable changes of short latency afferent inhibition in a group of mild cognitive impairment individuals.’, Front Aging Neurosci, 6 254. PubMed: 25295005
Ricciardi, L, et al. (2015), ‘Homotaurine in Parkinson’s disease.’, Neurol Sci, 36 (9), 1581-87. PubMed: 25894843
Russo, R, et al. (2015), ‘Intravitreal injection of forskolin, homotaurine, and L-carnosine affords neuroprotection to retinal ganglion cells following retinal ischemic injury.’, Mol Vis, 21 718-29. PubMed: 26167113
Spalletta, G, et al. (2016), ‘Homotaurine Effects on Hippocampal Volume Loss and Episodic Memory in Amnestic Mild Cognitive Impairment.’, J Alzheimers Dis, 50 (3), 807-16. PubMed: 26757035