TAT‐LBD‐Ngn2‐improved cognitive functions after global cerebral ischemia by enhancing neurogenesis

BACKGROUND: Stroke is the major cause of adult neurocognitive disorders (NCDs), and presents a significant burden on both of the families and society. To improve the cerebral injury, we generated a blood–brain barrier penetrating peptide TAT‐LBD‐Ngn2, in which Ngn2 (Neurogenin2) is a classical preneural gene that enhances neurogenesis, and neural precursor cells survival and differentiation. We previously demonstrated that it has a short‐term protective effect against cerebral ischemia‐reperfusion injury. However, it is uncertain if TAT‐LBD‐Ngn2 could promote neurogenesis to exhibit long‐term therapeutic impact. METHODS AND RESULTS: In present study, TAT‐LBD‐Ngn2 was administered for 14 or 28 days following bilateral common carotid arteries occlusion (BCCAO). After confirming that TAT‐LBD‐Ngn2 could cross the brain blood barrier and aggregate in the hippocampus, we conducted open field test, Morris water maze and contextual fear conditioning to examine the long‐term effect of TAT‐LBD‐Ngn2 on cognition. We discovered that TAT‐LBD‐Ngn2 significantly improved the spatial and contextual learning and memory on both days 14 and 28 after BCCAO, while TAT‐LBD‐Ngn2 exhibited anxiolytic effect only on day 14, but had no effect on locomotion. Using western blot and immunofluorescence, TAT‐LBD‐Ngn2 was also shown to promote neurogenesis, as evidenced by increased BrdU(+) and DCX(+) neurons in dentate gyrus. Meanwhile, TAT‐LBD‐Ngn2 elevated the expression of brain derived neurotrophic factor rather than nerve growth factor compared to the control group. CONCLUSIONS: Our findings revealed that TAT‐LBD‐Ngn2 could dramatically promote learning and memory in long term by facilitating neurogenesis in the hippocampus after global cerebral ischemia, indicating that TAT‐LBD‐Ngn2 may be an appealing candidate for treating poststroke NCD.