Nanotechnology-based therapeutics: new hope for ischemic cerebral stroke intervention

Ischemic cerebral stroke is a leading cause of death and disability globally.At present,thrombolytics,such as recombinant tissue-type plasminogen activator,are the only effective treatment for acute stroke.However,usage of thrombolytics has a strict therapeutic window and cannot be applied to a number of patients.Despite the promising effects of some neuroprotectants in preclinical studies,they failed in clinical trials as a result of poor pharmacokinetic properties,particularly with regard to solubility and permeability across the blood-brain barrier(BBB).Approaches for delivering these drugs by nanotechnologies may overcome these pharmacokinetic deficits and enhance their neuroprotective effects.However,issues such as potential side effects and biosafety properties currently limit clinical application of these approaches.In this article,we reviewed recent progress of nanotechnology-based interventions for stroke treatment,and in particular,summarized novel materials applied to synthesize nanocarriers,encapsulation with neuroprotectants,and factors impacting nanodrug bioactivities to provide a theoretical basis for the development of anti-stroke drugs.

DDAH1 promotes neurogenesis and neural repair in cerebral ischemia

Choline acetyltransferase(ChAT)-positive neurons in neural stem cell(NSC)niches can evoke adult neurogenesis(AN)and restore impaired brain function after injury,such as acute ischemic stroke(AIS).However,the relevant mechanism by which ChAT+neurons develop in NSC niches is poorly understood.Our RNA-seq analysis revealed that dimethylarginine dimethylaminohydrolase 1(DDAH1),a hydrolase for asymmetric NG,NG-dimethylarginine(ADMA),regulated genes responsible for the synthesis and transportation of acetylcholine(ACh)(Chat,Slc5a7 and Slc18a3)after stroke insult.The dual-luciferase reporter assay further suggested that DDAH1 controlled the activity of ChAT,possibly through hypoxia-inducible factor 1α(HIF-1α).KC7F2,an inhibitor of HIF-1α,abolished DDAH1-induced ChAT expression and suppressed neurogenesis.As expected,DDAH1 was clinically elevated in the blood of AIS patients and was positively correlated with AIS severity.By comparing the results among Ddah1 general knockout(KO)mice,transgenic(TG)mice and wild-type(WT)mice,we discovered that DDAH1 upregulated the proliferation and neural differentiation of NSCs in the subgranular zone(SGZ)under ischemic insult.As a result,DDAH1 may promote cognitive and motor function recovery against stroke impairment,while these neuroprotective effects are dramatically suppressed by NSC conditional knockout of Ddah1 in mice.