期刊
NEUROTHERAPEUTICS
卷 16, 期 3, 页码 725-740出版社
SPRINGER
DOI: 10.1007/s13311-019-00723-6
关键词
Angiotensin; Angiotensin receptor blocker; Hemorrhagic stroke; Intranasal; Cerebral amyloid angiopathy; Alzheimer's disease
资金
- Dr. Karl-Kuhn Foundation, Germany
- Interfaculty Centre for Pharmacogenomics and Pharma Research, Germany [15-0-0]
- Robert Bosch Stiftung, Stuttgart, Germany
The contribution of the local angiotensin receptor system to neuroinflammation, impaired neurogenesis, and amyloid beta (A beta) accumulation in Alzheimer's disease (AD) and in hypertension is consistent with the remarkable neuroprotection provided by angiotensin receptor blockers (ARBs) independent of their blood pressure-lowering effect. Considering the causal relationship between hypertension and AD and that targeting cerebrovascular pathology with ARBs does not necessarily require their systemic effects, we tested intranasal losartan in the rat model of chronic hypertension (spontaneously hypertensive stroke-prone rats, SHRSP). Intranasal losartan at a subdepressor dose decreased mortality, neuroinflammation, and perivascular content of A beta by enhancing key players in its metabolism and clearance, including insulin-degrading enzyme, neprilysin, and transthyretin. Furthermore, this treatment improved neurologic deficits and increased brain IL-10 concentration, hippocampal cell survival, neurogenesis, and choroid plexus cell proliferation in SHRSP. Losartan (1 mu M) also reduced LDH release from cultured astroglial cells in response to toxic glutamate concentrations. This effect was completely blunted by IL-10 antibodies. These findings suggest that intranasal ARB treatment is a neuroprotective, neurogenesis-inducing, and A beta-decreasing strategy for the treatment of hypertensive stroke and cerebral amyloid angiopathy acting at least partly through the IL-10 pathway.
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