Study summary · research use only
The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This review discusses developing small-molecule angiotensin IV (AngIV) analogs to treat Alzheimer's and Parkinson's diseases. The abstract summarizes the brain renin-angiotensin system's role in learning, memory and motor functions, emphasizing a link between AngIV and the AT4 receptor subtype, and notes controversy over whether the AT4 receptor is insulin-regulated aminopeptidase (IRAP) or coincides with the hepatocyte growth factor/c-Met receptor system. It describes synthesis of metabolically stable, blood-brain-barrier-penetrating AngIV-based compounds, including Dihexa, that the authors state facilitate memory and motor systems by augmenting synaptic connectivity through formation of new functional synapses.
Abstract
Alzheimer's (AD) and Parkinson's (PD) diseases are neurodegenerative diseases presently without effective drug treatments. AD is characterized by general cognitive impairment, difficulties with memory consolidation and retrieval, and with advanced stages episodes of agitation and anger. AD is increasing in frequency as life expectancy increases. Present FDA approved medications do little to slow disease progression and none address the underlying progressive loss of synaptic connections and neurons. New drug design approaches are needed beyond cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists. Patients with PD experience the symptomatic triad of bradykinesis, tremor-at-rest, and rigidity with the possibility of additional non-motor symptoms including sleep disturbances, depression, dementia, and autonomic nervous system failure. This review summarizes available information regarding the role of the brain renin-angiotensin system (RAS) in learning and memory and motor functions, with particular emphasis on research results suggesting a link between angiotensin IV (AngIV) interacting with the AT4 receptor subtype. Currently there is controversy over the identity of this AT4 receptor protein. Albiston and colleagues have offered convincing evidence that it is the insulin-regulated aminopeptidase (IRAP). Recently members of our laboratory have presented evidence that the brain AngIV/AT4 receptor system coincides with the brain hepatocyte growth factor/c-Met receptor system. In an effort to resolve this issue we have synthesized a number of small molecule AngIV-based compounds that are metabolically stable, penetrate the blood-brain barrier, and facilitate compromised memory and motor systems. These research efforts are described along with details concerning a recently synthesized molecule, Dihexa that shows promise in overcoming memory and motor dysfunctions by augmenting synaptic connectivity via the formation of new functional synapses.
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