Factors Contributing to Resistance to Ischemia-Reperfusion Injury in Olfactory Mitral Cells

Abstract

Brain ischemia-reperfusion (IR) injury is a critical pathological process that leads to extensive neuronal death, with hippocampal pyramidal cells, particularly those in the cornu Ammonis 1 (CA1) subfield, being highly vulnerable. Until now, human olfactory mitral cell resistance to IR injury has not been directly studied, but olfactory dysfunction in humans is frequently reported in systemic vascular conditions such as ischemic heart failure and may serve as an early clinical marker of neurological or cardiovascular disease. Mitral cells, the principal neurons of the olfactory bulb (OB), exhibit remarkable resistance to IR injury, suggesting the presence of unique molecular adaptations that support their survival under ischemic stress. Several factors may contribute to the resilience of mitral cells. They have a lower susceptibility to excitotoxicity, mitigating the harmful effects of excessive glutamate signaling. Additionally, they maintain efficient calcium homeostasis, preventing calcium overload-a major trigger for cell death in vulnerable neurons. Mitral cells may also express high baseline levels of antioxidant enzymes and their activities, counteracting oxidative stress. Their robust mitochondrial function enhances energy production and reduces susceptibility to metabolic failure. Furthermore, neuroprotective signaling pathways, including phosphatidylinositol-3-kinase (PI3K)/Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated antioxidative responses, further bolster their resistance. In addition to these intrinsic mechanisms, the unique microvascular architecture and metabolic support within the olfactory bulb provide an extra layer of protection. By comparing mitral cells to ischemia-sensitive neurons, key vulnerabilities-such as oxidative stress, excitotoxicity, calcium dysregulation, and mitochondrial dysfunction-can be identified and potentially mitigated in other brain regions. Understanding these molecular determinants of neuronal survival may offer valuable insights for developing novel neuroprotective strategies to combat IR injury in highly vulnerable areas, such as the hippocampus and cortex.

Keywords: antioxidant enzymes; excitotoxicity; metabolic failure; microvascular architecture; neuronal survival; neuroprotective signaling pathways.

Figure 1

Fluoro Jade B (F-J B) histofluorescence and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining in the main olfactory bulb (MOB; (A,B)) and hippocampal CA1 region (C,D) of the gerbil. F-J B and TUNEL-positive cells are rare in the MOB of the IR group, but many F-J B (white arrows) and TUNEL (black arrows)-positive cells are shown in the CA1 region after IR injury. EPL external plexiform layer; GCL granule cell layer; GL glomerular layer; SO stratum radiatum, SP stratum pyramidale; SR stratum radiatum. Scale Bars = 200 μm (A,B), 50 μm (C,D). This figure was published by Choi et al. (2010) [12].

Figure 2

Schematic representation of the translaminar organization of the olfactory bulb (OB) and its position. The olfactory receptor (or sensory) neurons (ORN) in the olfactory epithelium (OE) project to the glomerular cell layer (GL), where they connect to periglomerular (PG), as well as mitral (MC) and middle tufted (mTC) cells, which connect to granule cells (GC). The OB output propagates to the olfactory cortex through the MC and mTC axons in the lateral olfactory tract (LOT). EPL, external plexiform layer; GCL, granule cell layer. This figure was published by Cavarretta et al. (2018) [16].

Figure 3

Mechanisms of brain IR injury. This figure represents the cascade of pathological events occurring during IR injury. The interplay between excitotoxicity, oxidative stress, inflammation, and mitochondrial dysfunction contributes to neuronal death and brain damage. Excessive Ca²⁺ influx and ROS lead to mitochondrial dysfunction and the opening of the mitochondrial permeability transition pore (mPTP). Cytochrome C is released into the cytoplasm and activates caspases, which drive apoptosis. This figure was originally published by Zheng et al. (2023) [6].

Figure 4

(A) Arterial supply of the OB and olfactory nerve. The OB is mainly supplied by the olfactory artery, a branch of the anterior cerebral artery. This figure was published by Hendrix et al. (2014). (B) Three-dimensional reconstruction of vessels and glomeruli. Vessel colors vary with depth, and glomeruli are indicated in light blue. This figure was published by Lecoq et al. (2009) [26].