Adipokines as novel therapy to promote functional recovery after experimental traumatic brain injury

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

Traumatic brain injury (TBI) can elicit cognitive disabilities due to mechanical shearing of the vascular supply, damage of the neurovascular unit, and secondary cascades of endothelial and microglial inflammation, and neurodegeneration. TBI increases the risk of clinical dementia, including Vascular Cognitive Impairment and Dementia (VCID), by 1.6 to 3.7-fold, as it directly damages blood vessels and reduces cerebral blood flow. The severity of neurovascular injury after TBI is correlated with the increased risk of developing VCID, with more severe injuries bearing a greater impact on brain vasculature. There is thus an urgent, unmet need for drugs that protect neurons and mitigate neurovascular damage-related cognitive impairments when given after TBI. To fill this gap, we will capitalize on new pilot data on long-term salutary effects of a diffusible hormone, adiponectin. Adiponectin is a brain-penetrant adipocytokine. It binds to adipoR1/R2 receptors to upregulate AMPK and PPARα pathways, exerting powerful anti-inflammatory and prosurvival effects. Adiponectin knockout (KO) activates inflammation and worsens memory loss and Alzheimer’s-related pathologies. We found that adiponectin deficiency boosts inflammatory cascades, neuron loss, and cognitive deficits in a vascular dementia model, whereas a small-molecule agonist of adiponectin receptors, AdipoRon, alleviated these pathologies. However, the long-term impact and mechanism of action of adiponectin in chronic stages of TBI are unknown. We have obtained exciting pilot data supporting remarkable long-term beneficial effects of adiponectin receptor activation in experimental TBI. After AdipoRon treatment, single-cell RNAseq of microglia (Mi), monocyte-derived macrophages (MΦ), cerebral endothelial cells (ECs), and oligodendrocytes (OLs) shows profound transcriptomic changes in favor of neuronal and cerebrovascular protection, angiogenesis, and tissue repair. Thus, our proposal will test the hypothesis that Adiponectin improves neurological outcomes after traumatic shearing of the neurovascular unit by diverse mechanisms: 1) Protection against axonal damage and hippocampal neuron loss in early injury stages via the release of growth hormone from Mi/MΦ and ECs, 2) restoration of white matter and cognitive functional recovery in chronic injury stages via pro-repair OLs and inflammation-resolving Mi/MΦ. In Aim 1, we will test the long-term therapeutic potential of a selective adipoR1/R2 agonist against neurovascular unit damage and cognitive deficits in a robust model of dementia after TBI. In Aim 2, we will test if adiponectin receptor activation attenuates acute axonal injury and hippocampal pyramidal neuron loss after TBI by releasing neuroprotective growth hormone from Mi/MΦ. In Aim 3, we will test if the pro-repair actions of OLs and inflammation-resolving Mi/MΦ contribute to AdipoRon-afforded white matter restoration and long-term recovery from severe cognitive deficits in TBI-induced neurovascular injury. Completion of the Aims will enhance our understanding of the molecular and cellular mechanisms underlying cognitive decline after neurovascular injury, and open new translational avenues for lowering the risk of VCID.