Post-stroke brain can be protected by modulating the lncRNA FosDT

• Published in: Journal of cerebral blood flow and metabolism 2024-02, Vol.44 (2), p.239-251
• Main Authors: Mehta, Suresh L, Chelluboina, Bharath, Morris-Blanco, Kahlilia C, Bathula, Saivenkateshkomal, Jeong, Soomin, Arruri, Vijay, Davis, Charles K, Vemuganti, Raghu
• Format: Article
• Language: English
• Subjects: Animals; Brain - metabolism; Brain Ischemia; Diabetes Mellitus, Experimental; Female; Infarction, Middle Cerebral Artery - complications; Male; Mice; Neuroprotective Agents - pharmacology; NF-kappa B - metabolism; Original; Rats; Rats, Inbred SHR; RNA, Long Noncoding - genetics; RNA, Small Interfering - genetics; RNA, Small Interfering - therapeutic use; Stroke - complications
• ISSN: 0271-678X; 1559-7016; 1559-7016
• DOI: 10.1177/0271678X231212378

We previously showed that knockdown or deletion of Fos downstream transcript (FosDT; a stroke-induced brain-specific long noncoding RNA) is neuroprotective. We presently tested the therapeutic potential of FosDT siRNA in rodents subjected to transient middle cerebral artery occlusion (MCAO) using the Stroke Treatment Academic Industry Roundtable criteria, including sex, age, species, and comorbidity. FosDT siRNA (IV) given at 30 min of reperfusion significantly improved motor function recovery (rotarod test, beam walk test, and adhesive removal test) and reduced infarct size in adult and aged spontaneously hypertensive rats of both sexes. FosDT siRNA administered in a delayed fashion (3.5 h of reperfusion following 1 h transient MCAO) also significantly improved motor function recovery and decreased infarct volume. Furthermore, FosDT siRNA enhanced post-stroke functional recovery in normal and diabetic mice. Mechanistically, FosDT triggered post-ischemic neuronal damage via the transcription factor REST as REST siRNA mitigated the enhanced functional outcome in FosDT−/− rats. Additionally, NF-κB regulated FosDT expression as NF-κB inhibitor BAY 11-7082 significantly decreased post-ischemic FosDT induction. Thus, FosDT is a promising target with a favorable therapeutic window to mitigate secondary brain damage and facilitate recovery after stroke regardless of sex, age, species, and comorbidity.