Preconditioned neurons with NaB and nicorandil, a favorable source for stroke cell therapy

Abstract

Poor survival of stem cells in the harsh microenvironment at the site of stroke, especially during acute phase of injury, remains a serious obstacle to achieve the desired prognosis. We hypothesized that combined treatment of neural stem cells (NSCs) with small molecules would precondition them to become robust and survive better as compared with the native nonpreconditioned cells. Mouse ganglionic NSCs were isolated, cultured, and characterized. The cells were preconditioned by treatment with sodium butyrate (NaB) and nicorandil (Nico) and transplanted in an experimentally induced stroke model. Sham-operated animals without treatment or animals with experimental stroke treated with basal medium, native NSCs, NSCs preconditioned with NaB or Nico alone were used as controls. The tissue samples and cells with different treatments were used to measure brain-tissue-derived neurotrophic factor (BDNF) level and the activity of phosphatidylinositol-3 kinase (PI3K), apurinic/apyrimidinic endonuclease 1 (APE1), and nuclear factor-κB (NF-κB) p50 both in vitro and in vivo, respectively. Additionally, survival of the cells and recovery indices for stroke were studied. The combined treatment with NaB + Nico resulted in increased BDNF level and higher PI3K, APE1, and the downstream NF-κB activation, which were blocked by pretreatment with their respective inhibitors. Donor cell survival increased postengraftment as assessed by 5-bromo-2'-deoxyuridine immunostaining and reduced Terminal deoxynucleotide transferase dUTP Nick End Labeling positivity at the site of engraftment. There was reduction in proinflammatory cytokines and infiltration of both GFAP and CD68 at the injury site. There was reduction in the infarct size and neurological function was preserved in the preconditioned cell treatment group. Our preconditioning approach with small molecules effectively improved the survival as well as functionality of NSCs.

Mesenchymal stem cells’ “garbage bags” at work: Treating radial nerve injury with mesenchymal stem cell-derived exosomes

“…Their reparability is via multifactorial mechanisms encompassing neuroprotection to differentiation to adopt morphofunctional competent neural cells besides the release of secretome containing neurotrophic factors and exosomes rich in the bioactive payload of microRNAs (miRNAs), enzymes, and protein[ 39 ], which will be discussed in the following sections. To enhance their stemness and reparability, they have been combined with NSCs, preconditioned to enhance their paracrine activity, or genetically modified to serve as a source of neurotrophic factors as paracrine factors[ 40 , 41 ].…”

Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke

“…An increase in anti-inflammatory mediators and suppression of pro-inflammatory mediators in pretreated NSC cells contributes to inhibiting the inflammatory response. Neurological function remains stable in the preconditioning treatment, illustrating that a small molecule preconditioning approach improves survival of stem cells and inhibits microglial activation [ 165 ].…”

Nicorandil attenuates cognitive impairment after traumatic brain injury via inhibiting oxidative stress and inflammation: Involvement of BDNF and NGF

“…Nicorandil, an ATP-sensitive potassium (KATP) channel opener, possesses antioxidative, anti-inflammatory, and neuroprotective activities (Abdelkader et al, 2020;Bedair et al, 2023;Hosseini et al, 2018).…”

“…Nicorandil, an ATP‐sensitive potassium (KATP) channel opener, possesses antioxidative, anti‐inflammatory, and neuroprotective activities (Abdelkader et al., 2020 ; Bedair et al., 2023 ; Hosseini et al., 2018 ). Researches have elucidated that nicorandil promotes cerebral blood flow, attenuates neural death by suppressing oxidative stress and inflammatory effects, and preserves the integrity of the blood‐brain barrier, thereby exerting neuroprotective effects (Hosseini et al., 2018 ; Kotoda et al., 2018 ).…”

“…Nicorandil, an ATP‐sensitive potassium (KATP) channel opener, possesses antioxidative, anti‐inflammatory, and neuroprotective activities (Abdelkader et al., 2020 ; Bedair et al., 2023 ; Hosseini et al., 2018 ). Researches have elucidated that nicorandil promotes cerebral blood flow, attenuates neural death by suppressing oxidative stress and inflammatory effects, and preserves the integrity of the blood‐brain barrier, thereby exerting neuroprotective effects (Hosseini et al., 2018 ; Kotoda et al., 2018 ). Intriguingly, current investigations suggest that activation of the KATP channel significantly contributes to cerebrovasodilation and plays a pivotal role in autoregulation both of which are impaired in the context of TBI (Pastor et al., 2019 ).…”