Selegiline promotes NOTCH-JAGGED signaling in astrocytes of the peri-infarct region and improves the functional integrity of the neurovascular unit in a rat model of focal ischemia

Abstract

Purpose: Our experiments aimed at exploring potential neurorestorative mechanisms of selegiline, a compound routinely used in the treatment of Parkinson's disease and previously shown to improve the functional recovery of stroke patients. Methods: Selegiline was administered continuously via osmotic mini-pumps between 48 and 216 hours following middle cerebral artery occlusion (MCAO) in rats. Twenty-four hours before sacrifice, the animals underwent magnetic resonance imaging (MRI). After decapitation, the peri-infarct region was dissected to perform a TAQMAN array gene expression study, and brains were fixed for immunolabeling. Results: In addition to the previously known induction of anti-apoptosis genes, selegiline significantly increased the mRNA level of Notch 1 receptor and its ligand Jagged 1. Immunohistochemistry demonstrated elevated Notch 1 and Jagged 1 immunoreactivities in the peri-infarct region. Double labeling with glial markers revealed that both Notch 1 and Jagged 1 were expressed in astrocytes but not in microglia. MRI examination indicated significantly reduced edema in selegiline-treated rats compared to control MCAO rats, and increased capillary network density was found in the peri-infarct region of the selegiline-treated animals. Conclusion: Our results suggest that selegiline treatment enhances Notch-Jagged signaling in astrocytes, reduces peri-lesional edema and potentially helps preserve the capillary network following focal ischemia.

Notch signalling suppresses regulatory T‐cell function in murine experimental autoimmune uveitis

“…Previous studies indicated expression of JAG and DLL on reactive brain astrocytes, and astrocytes can induce Notch signalling by themselves or with other cell types such as neural stem cells. [31][32][33][34] Moreover, a recent study demonstrated that optic nerve astrocytes express JAG1 with no significant expression of DLL. 35 Since retinal astrocytes are immigrants from the optic nerve, 36 it is possible that they also express Notch ligands.…”

Neurovascular Unit: A critical role in ischemic stroke

“…Cilostazol is a commonly used antiplatelet drug, which prevents the pathological detachment of astrocyte foot processes or PCs and also stimulates VEGFR2 expression and PC proliferation, thereby protecting the NVU integrity and promoting neurovascular protection 104 . Notch‐Jagged signaling in astrocytes is increased in selegiline‐treated MCAO rats compared with control, helping to preserve the capillary network after IS 105 . Treatment with tPA inhibits the secretion of glial cell‐derived trophic factors and damages PCs, but edaravone can reverse the damage, and maintains NVU integrity after tPA treatment 106 .…”

Transporter-Mediated Delivery of Small Molecule Drugs to the Brain: A Critical Mechanism That Can Advance Therapeutic Development for Ischemic Stroke

“…The exact mechanism of memantine transport across the BBB requires more detailed investigation; however, therapeutic targeting of memantine to the CNS via OCT-dependent drug delivery may prove to be an effective mechanism to enhance the utility of this neuroprotective drug in treatment of ischemic stroke. Other OCT transport substrates that may be effective as stroke therapeutics include the D2/D3 receptor agonist pramipexole [84,85], the monoamine oxidase inhibitor selegiline [86], and the nicotinic receptor agonist varenicline [87]. Further data is required to determine the functional role of OCT isoforms expressed at the BBB in the setting of ischemic stroke.…”