As mentioned above, treatment of 5xFAD transgenic mice (which acc

As mentioned above, treatment of 5xFAD transgenic mice (which accumulate amyloid burden at early ages) with a combination of L-DOPS and atomoxetine elevated brain NE levels, increased expression of A?? clearance enzymes and brain-derived neurotrophic factor, sellekchem reduced inflammatory changes and A?? burden, and improved spatial memory [59]. In clinical studies, atomoxetine has also been shown to improve working memory, response inhibition and other executive functions in patients with attention-deficit hyperactivity disorder [83-86]. Several small studies have examined atomoxetine treatment in older patients with neurodegenerative disease to assess safety, tolerability and symptomatic effects. Marsh and colleagues studied 12 patients with Parkinson’s disease with doses up to 100 mg daily (mean tolerated dose 89.

6 mg), with excellent safety, tolerability and improved executive function [82]. Weintraub and colleagues found that 80 mg once daily was well tolerated by Parkinson’s disease subjects as a treatment for depression; only four of 29 patients withdrew because of adverse effects [87]. Although atomoxetine was ineffective for the treatment of depression in the study, atomoxetine was associated with improvement of global cognition. A 6-month phase II trial in mild to moderate AD tested up to 80 mg atomoxetine once daily in 47 subjects [88]. Although atomoxetine was well tolerated (only five subjects withdrew because of adverse effects), there were no significant improvements in cognitive function, global clinical impression or neuropsychiatric symptoms.

However, this study was not powered for clinical efficacy and, more importantly, did not investigate the potential anti-inflammatory neuroprotective role of NE pharmacotherapy. Moreover, since patients with mild to moderate AD already have extensive neurodegeneration, most investigators now realize the best chance for neuroprotection will come from earlier intervention. Logical next steps would therefore be to test NE pharmacotherapies for their potential anti-inflammatory and other neuroprotective mechanisms in phase II trials with individuals with preclinical or early clinical (that is, MCI) stages of AD. For example, it would be important to evaluate the effect of NE-based treatments such as atomoxetine and L-DOPS on biomarkers of AD pathology and inflammation [49,50,89,90].

A potential target would be cerebrospinal fluid inflammatory markers, which have been used successfully as surrogate markers of drug response in multiple sclerosis [91,92] and are among novel biomarkers that distinguish MCI and AD from other neurodegenerative Dacomitinib diseases and correlate with both baseline cognitive impairment and subsequent cognitive decline [50]. In sum, there Vandetanib structure is a growing body of evidence linking LC neurodegeneration and altered NE neurotransmission to the pathogenesis of AD, in addition to the long-established links with cognitive and behavioral symptoms.

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