Introduction: Therapeutic strategies utilizing neurotrophins hold great promise for treating ischemic brain injuries. However, their clinical application is limited due to low bioavailability, which complicates delivery to damaged neural tissues. To address this challenge, the Center for Innovative and Emerging Biomedical and Pharmaceutical Technologies has developed novel systemically active dipeptide mimics of NGF (GK-2) and BDNF (GSB-106). In this study, we aimed to investigate whether the neuroprotective effects of these compounds in the middle cerebral artery occlusion (MCAO) model of ischemia are related to their influence on neurogenesis. Methods: Following MCAO surgery, rats received intraperitoneal injections of GK-2 (0.5 mg/kg) or GSB-106 (0.1 mg/kg) daily for 7 days. Neurogenesis in the hippocampal subgranular zone (SGZ) was evaluated 8 days post-MCAO by immunohistochemistry using BrdU and doublecortin (Dcx) as markers. Results: A Significant increase in the number of BrdU-containing cells in the MCAO, MCAO+GK-2, and MCAO+GSB-106 groups was revealed (by 217, 172, and 179%, respectively). The number of Dcx-positive cells also increased in the MCAO and MCAO+GSB-106 groups (by 56 and 97%, respectively). A notable prevalence of morphologically abnormal Dcx-positive cells with ectopic dendrite orientation was observed in the MCAO group and the MCAO+GK-2 group (by 63 and 27%, respectively), but not in the MCAO+GSB-106 group. A dramatic 200% increase in ectopic Dcx+ cells in the hippocampal hilus was documented in the ischemic hemisphere of MCAO rats. This deleterious effect was mitigated by treatment with GK-2 (100%) or GSB-106 (87%). Discussion: Numerous studies demonstrate the involvement of BDNF/TrkB and NGF/TrkA and p75NTR in neurogenesis within the hippocampus; therefore, it is reasonable to hypothesize that the application of BDNF and NGF mimetics could be crucial for developing novel stroke treatment strategies. Conclusion: The dipeptides GK-2 and GSB-106, mimicking NGF and BDNF, respectively, attenuated or prevented some MCAO-induced abnormalities in neurogenesis in rats. These findings suggest their potential to modulate post-ischemic neurogenesis and offer a promising therapeutic approach for ischemic brain injury.
Stepanichev et al. (Wed,) studied this question.