Vascular α1A Adrenergic Receptors as a Potential Therapeutic Target for IPAD in Alzheimer’s Disease

Abstract

Drainage of interstitial fluid from the brain occurs via the intramural periarterial drainage (IPAD) pathways along the basement membranes of cerebral capillaries and arteries against the direction of blood flow into the brain. The cerebrovascular smooth muscle cells (SMCs) provide the motive force for driving IPAD, and their decrease in function may explain the deposition of amyloid-beta as cerebral amyloid angiopathy (CAA), a key feature of Alzheimer’s disease. The α-adrenoceptor subtype α1A is abundant in the brain, but its distribution in the cerebral vessels is unclear. We analysed cultured human cerebrovascular SMCs and young, old and CAA human brains for (a) the presence of α1A receptor and (b) the distribution of the α1A receptor within the cerebral vessels. The α1A receptor was present on the wall of cerebrovascular SMCs. No significant changes were observed in the vascular expression of the α1A-adrenergic receptor in young, old and CAA cases. The pattern of vascular staining appeared less punctate and more diffuse with ageing and CAA. Our results show that the α1A-adrenergic receptor is preserved in cerebral vessels with ageing and in CAA and is expressed on cerebrovascular smooth muscle cells, suggesting that vascular adrenergic receptors may hold potential for therapeutic targeting of IPAD.

Vasoprotective Endothelial Effects of Chronic Cannabidiol Treatment and Its Influence on the Endocannabinoid System in Rats with Primary and Secondary Hypertension

“…The histological preparations were evaluated using a BX43 light microscope equipped with an Olympus DP12 digital camera under a magnification of 200× (20× lens and 10× eyepiece) and documented. In each blood vessel the percentage area stained was measured using the ImageJ software [67], and an average was calculated from the values obtained from the five vessels per case. To calculate the percentage area of staining in the vessel wall, ImageJ software version 1.53c (Java 1.8.0_172) (NIH, Bethesda, MD, USA) was used to draw around the artery, and the area stained was divided by the total area to give a percentage staining.…”

Conversion from cilostazol to OPC‐13015 linked to mitigation of cognitive impairment

“…to modulate vasomotion, 3 including the stimulation of α1A adrenergic receptors 35 and the inhibition of PDE-3. 4,36 An amelioration of cerebrovascular Aβ accumulation by cilostazol treatment has been demonstrated in several AD model mouse lines.…”

“…This finding may be partially explained by the excessive antibody‐solubilized senile plaque Aβ that is redeposited in the cerebral vasculature, as well as impaired Aβ clearance through IPAD, 32 demonstrating the necessity of promoting IPAD 2 . Because the driving force of IPAD is the spontaneous contraction and relaxation of cerebrovascular SMCs, 33,34 several approaches have been proposed to modulate vasomotion, 3 including the stimulation of α1A adrenergic receptors 35 and the inhibition of PDE‐3 4,36 . An amelioration of cerebrovascular Aβ accumulation by cilostazol treatment has been demonstrated in several AD model mouse lines 4,36 .…”

Cannabidiol Improves Antioxidant Capacity and Reduces Inflammation in the Lungs of Rats with Monocrotaline-Induced Pulmonary Hypertension

“…The results of staining were submitted for evaluation in an Olympus BX43 microscope with Olympus DP12 camera. In each lung sample, the percentage area stained was measured using the ImageJ software version 1.53c (NIH, Bethesda, MD, USA) [ 49 ], and an average was calculated from the values obtained from the six lungs per group. In order to calculate the percentage area of staining in the lungs, the area stained was divided by the total area of lung tissue to obtain a percentage staining.…”