Diabetes mellitus (DM) is a common metabolic disease in the middle-aged and older population, and is associated with cognitive impairment and an increased risk of developing dementia. The glymphatic system is a recently characterised brain-wide cerebrospinal fluid and interstitial fluid drainage pathway that enables the clearance of interstitial metabolic waste from the brain parenchyma. Emerging data suggest that DM and ageing impair the glymphatic system, leading to accumulation of metabolic wastes including amyloid-β within the brain parenchyma, and consequently provoking cognitive dysfunction. In this review, we concisely discuss recent findings regarding the role of the glymphatic system in DM and ageing associated cognitive impairment.

The glymphatic system is a newly discovered waste drainage pathway in the brain; it plays an important role in many neurological diseases. Ongoing research utilizing various cerebrospinal fluid tracer infusions, either directly or indirectly into the brain parenchyma, is investigating clearance pathways by using distinct imaging techniques. In the present review, we discuss the role of the glymphatic system in various neurological diseases and efflux pathways of brain waste clearance based on current evidence and controversies. We mainly focus on new magnetic resonance imaging (MRI) modeling techniques, along with traditional computational modeling, for a better understanding of the glymphatic system function. Future sophisticated modeling techniques hold the potential to generate quantitative maps for glymphatic system parameters that could contribute to the diagnosis, monitoring, and prognosis of neurological diseases. The non-invasive nature of MRI may provide a safe and effective way to translate glymphatic system measurements from bench-to-bedside.

Our previous work in acute ischemic stroke and TBI models focused on efficacy and pharmacological parameters of Cerebrolysin®. In this prospective, randomized, blinded, placebo-controlled study we compared efficacy of neuropeptide preparations with putative neurotrophic potential to the reference product Cerebrolysin® by assessing functional outcome and lesion volumes after embolic stroke in a rodent model. Male Wistar rats were subjected to embolic right middle cerebral artery occlusion and were treated with: 1) Cognistar® (Cerebroprotein Hydrolysate) 2.5 ml/kg, 2) Cerebrolysat® 2.5 ml/kg, 3) Cortexin® 1.7 mg/kg, 4) Cerebrolysin® 2.5 ml/kg, or 5) 1 ml of saline according to a pre-generated randomization plan. Dosages were defined according to the packet leaflet of the corresponding preparation and were adapted to the animal model as previously described. All enrolled rats received intraperitoneal injections once daily for 10 consecutive days, starting 4 h after occlusion. Functional outcome was assessed once weekly over four weeks by using a battery of behavioral tests. Infarct volume was measured four weeks after occlusion. Generalized Estimation Equations (GEE) was performed to study the treatment effect on overall functional recovery at day 28 (primary outcome), compared to saline controls. Similar functional outcome was observed for saline control, Cognistar®, Cerebrolysat® and Cortexin®; in contrast, a significantly improved neurological outcome was observed with Cerebrolysin® treatment in comparison to saline as well as to the comparator drug treatment (p < .002). However, there was no significant difference in lesion volumes between rats treated with either Cortexin® (33.5 ± 1.9%), Cerebrolysat® (28.5 ± 2.4%), Cognistar® (34.7 ± 2.0%), or Cerebrolysin® (26.5 ± 2.3%) compared to saline-treated rats (30.8 ± 2.1%). Among all tested neuropeptide preparations, Cerebrolysin® was the only agent that was associated with a significant improvement of neurological outcome after stroke.

Background and Purpose—: Thrombolytic treatment of acute ischemic stroke with tPA (tissue-type plasminogen activator) is hampered by its narrow therapeutic window and potential hemorrhagic complication. Vepoloxamer is a nonionic surfactant that exerts potent hemorheologic and antithrombotic properties in various thrombotic diseases. The current study investigated the effect of vepoloxamer on tPA treatment in a rat model of embolic stroke. Methods—: Male Wistar rats subjected to embolic middle cerebral artery occlusion were treated with the combination of vepoloxamer and tPA, vepoloxamer alone, tPA alone, or saline initiated 4 hours after middle cerebral artery occlusion. Results—: Monotherapy with tPA did not reduce infarct volume, and adversely potentiated microvascular thrombosis and vascular leakage compared with the saline treatment. Vepoloxamer monotherapy reduced infarct volume by 25% and improved brain perfusion. However, the combination treatment with vepoloxamer and tPA significantly reduced infarct volume by 32% and improved neurological function, without increasing the incidence of gross hemorrhage. Compared with vepoloxamer alone, the combination treatment with vepoloxamer and tPA robustly reduced secondary thrombosis and tPA-augmented microvascular leakage and further improved brain perfusion, which was associated with substantial reductions of serum active PAI-1 (plasminogen activator inhibitor-1) level and tPA-upregulated PAI-1 in the ischemic brain. Mechanistically, exosomes derived from platelets of ischemic rats treated with tPA-augmented cerebral endothelial barrier permeability and elevated protein levels of PAI-1 and TF (tissue factor) in the endothelial cells, whereas exosomes derived from platelets of rats subjected to the combination treatment with vepoloxamer and tPA diminished endothelial permeability augmented by tPA and fibrin and reduced PAI-1 and TF levels in the endothelial cells. Conclusions—: The combination treatment with vepoloxamer and tPA exerts potent thrombolytic effects in rats subjected to acute ischemic stroke. Vepoloxamer reduces tPA-aggravated prothrombotic effect of platelet-derived exosomes on cerebral endothelial cells, which may contribute to the therapeutic effect of the combination treatment.