Abstract
Transient forebrain ischemia induces delayed death of the hippocampal pyramidal neurons, particularly in the CA2 and medial CA1 area. Early pharmacological inhibition of inflammatory response can ameliorate neuronal death, but it also inhibits processes leading to tissue regeneration. Therefore, research efforts are now directed to modulation of post-ischemic inflammation, with the aim to promote beneficial effects of inflammation and limit adverse effects. Transcription factor NF-κB plays a key role in the inflammation and cell survival/apoptosis pathways. In the brain, NF-κB is predominantly found in the form of a heterodimer of p65 (RelA) and p50 subunit, where p65 has a transactivation domain while p50 is chiefly involved in DNA binding. In this study, we subjected middle-aged Nfkb1 knockout mice (lacking p50 subunit) and wild-type controls of both sexs to 17 min of transient forebrain ischemia and assessed mouse performance in a panel of behavioral tests after two weeks of post-operative recovery. We found that ischemia failed to induce clear memory and motor deficits, but affected spontaneous locomotion in genotype- and sex-specific way. We also show that both the lack of the NF-κB p50 subunit and female sex independently protected CA2 hippocampal neurons from ischemia-induced cell death. Additionally, the NF-κB p50 subunit deficiency significantly reduced ischemia-induced microgliosis, astrogliosis, and neurogenesis. Lower levels of hippocampal microgliosis significantly correlated with faster spatial learning. We conclude that NF-κB regulates the outcome of transient forebrain ischemia in middle-aged subjects in a sex-specific way, having an impact not only on neuronal death but also specific inflammatory responses and neurogenesis.
Highlights
Transient forebrain ischemia induces delayed death of the hippocampal pyramidal neurons, in the CA2 and medial CA1 area
Transient forebrain ischemia failed to induce significant memory and motor deficits To investigate whether Nfkb1 gene deficiency has an effect on neurological outcome following transient forebrain ischemia, we subjected large cohorts of male and female Nfkb1-wt and Nfkb1-ko mice to 17 min of bilateral common carotid artery occlusion (BCCAo)
We show for the first time that Nfkb1 gene deficiency protected CA2 hippocampal neurons from forebrain ischemia-induced death in middle-aged mice when using long-term follow-up
Summary
Transient forebrain ischemia induces delayed death of the hippocampal pyramidal neurons, in the CA2 and medial CA1 area. We show that both the lack of the NF-κB p50 subunit and female sex independently protected CA2 hippocampal neurons from ischemia-induced cell death. We conclude that NF-κB regulates the outcome of transient forebrain ischemia in middle-aged subjects in a sex-specific way, having an impact on neuronal death and specific inflammatory responses and neurogenesis. A transient forebrain ischemia is defined as a relatively homogeneous temporary reduction in the blood supply to the forebrain leading to depletion of oxygen and glucose in the brain tissue. In humans, this is often caused by cardiac arrest with subsequent cardiopulmonary resuscitation or occurs during cardiac bypass surgery. Pharmacological inhibition of inflammatory response reduces strokeinduced proliferation of neural progenitor cells [16, 17]
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