Intranasal Losartan Decreases Perivascular Beta Amyloid, Inflammation, and the Decline of Neurogenesis in Hypertensive Rats

Abstract

The contribution of the local angiotensin receptor system to neuroinflammation, impaired neurogenesis, and amyloid beta (Aβ) 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 strokeprone rats, SHRSP). Intranasal losartan at a subdepressor dose decreased mortality, neuroinflammation, and perivascular content of Aβ 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 μM) 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 Aβ-decreasing strategy for the treatment of hypertensive stroke and cerebral amyloid angiopathy acting at least partly through the IL-10 pathway.

Inhibition of microglial activation in rats attenuates paraventricular nucleus inflammation in Gαi2 protein‐dependent, salt‐sensitive hypertension

“…Levels of IL-10 were downregulated at both the mRNA and protein levels during G i 2 ODN infusion on the HS diet, suggesting a decrease in neuroprotective signalling in the PVN, consistent with literature suggesting that IL-10 is protective against other forms of hypertension (Drews et al, 2019;Segiet et al, 2019). Lastly, minocycline administration, which lowered blood pressure and plasma NA levels in G i 2 ODN-infused rats on a HS diet, restored mRNA levels of PIC and anti-inflammatory cytokines to baseline, suggesting a direct role of neuroinflammation in G i 2 protein-dependent hypertension.…”

Interaction between Angiotensin Type 1, Type 2, and Mas Receptors to Regulate Adult Neurogenesis in the Brain Ventricular–Subventricular Zone

“…However, previous studies have also shown that ROS derived from NADPH-oxidase activation contribute to the self-renewal [78] and lineage determination in NSCs [79], and that AT1 receptors have an important role in progenitor cell proliferation [80]. Other studies have observed that blockage of AT1 receptors with different antagonists such as candesartan, valsartan, or losartan induced proliferation and neurogenesis in the dentate gyrus [25,26,81], but also that treatment with AT1 antagonists or angiotensin converting enzyme inhibitors diminishes neurogenesis [27,28,[82][83][84], or that AT1 blockade does not affect hippocampal neurogenesis [85,86]. There are also controversial results on the effects of AT2 receptors.…”

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

“…Further, increased proliferation and generation of neuroblasts were shown in wild type mice with the administration of AT 2 R agonist C21 (Garcia-Garrote et al, 2019). Similarly, it was shown that AT 1 R blockade can enhance hippocampal neurogenesis in hypertensive state (Bhat et al, 2018;Drews et al, 2019). Interestingly, neurogenesis was enhanced in hippocampal dentate gyrus of adult rodents exposed to short-term heat as a result of activation of AT 1 R due to increase in Ang II (Koyama et al, 2018).…”