Tantalizing pieces of evidence continue selleck ARQ197 to support the idea of increasing NE to treat cognitive impairment in AD. For example, clonidine – which suppresses NE release by activating the ??2-adrenergic autoreceptor – impairs short-term recognition memory in patients [75], suggesting that facilitating NE release may be beneficial. The same group determined that clonidine could also enhance spatial working memory in AD patients [76], however, highlighting the complexity of these processes. Several clinical studies examining hypertension suggest that ??-blockers may have therapeutic effects on inflammation and dementia. Dementia incidence and annual rate of cognitive decline tend to be lower in older patients that take ??-blockers for hypertension [77-79].

The ??1-antagonists nevibolol and metoprolol have been shown to attenuate the release of atherosclerotic inflammatory markers such as soluble intercellular adhesion molecule-1 in humans after 1 year of treatment [80]. Since hypertension itself is a risk factor for AD, however, it is difficult to know whether the benefits of ??-blockade are mediated by direct effects on neuroinflammation or are indirect effects mediated by control of hypertension. Overall, the strong links between LC/NE loss in AD and disease progression in AD animal models combined with human clinical and preclinical data demonstrate the exciting disease-modifying potential of drugs that modulate NE levels. The urgent and essential next step is to translate these discoveries to humans.

Although NE pharmacotherapies are widely used in medicine, drugs that regulate NE transmission in the brain could have complicated effects Drug_discovery in Afatinib Sigma AD. The integrity of the LC and pharmacological responsiveness in prodromal stages of AD are poorly understood. While preclinical studies suggest potential for NE-enhancing therapies to reduce neuroinflammation and amyloid burden and to ameliorate cognitive impairment, clinical observations in AD patients also suggest the potential to impact noncognitive symptoms of AD including mood, apathy, disinhibition, sleep, agitation and aggression [81,82]. Several NE pharmacotherapies are already used in clinical practice for a variety of neurological and psychiatric disorders, including attention-deficit disorder, depression and orthostatic hypotension. NET inhibitors such as atomoxetine, a US Food and Drug Administration-approved drug that is a widely prescribed treatment for children and adults with attention-deficit hyperactive disorder, and reboxetine, approved in many countries around the world for depression, have been used safely in older subjects.