Radiation-induced neuroinflammation: a potential protective role for poly(ADP-ribose) polymerase inhibitors?

Abstract

Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbor a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response (DDR) and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50%-90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation-induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DDR and subsequent neuroinflammation. PARP inhibitors (PARPi) have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least 3 compounds being evaluated in clinical trials. We propose that concomitant use of PARPi could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumor control by enhancing radiosensitivity.

Keywords: DNA damage; glioblastoma; microglia; neuroinflammation; neuroprotection; radiation therapy.

Figure 1.

Overview of the impact of ionizing radiation on key CNS cell populations. In response to cellular damage caused by IR, neurons and endothelial cells secrete alarmin molecules (eg, HMGB1) which trigger microglial activation, while radiation-induced DNA damage within microglia themselves also promotes their activation. Proinflammatory molecules secreted by activated microglia, such as IL-6 and TNFα, can prevent neural stem cell differentiation, impacting on neurogenesis and astrocyte development. Inflammatory mediators also stimulate increased expression of endothelial adhesion markers such as ICAM-1 and P-selectin, leading to permeabilization of the blood–brain barrier (BBB) and infiltration of peripheral immune cells into the brain parenchyma. This is further enhanced by the secretion of chemoattractant molecules (CCL2) by activated microglia. CNS, central nervous system; HMGB1, high mobility group box 1; ICAM-1, intercellular adhesion molecule 1; IL-6, interleukin-6; IR, irradiation; TNFα, tumor necrosis factor α.

Figure 2.

PARP-mediated neuroinflammation in microglia. Following radiation-induced DNA damage, PARP binds to SSBs and recruits BER proteins to induce PARylation and initiate DNA repair. During this process, PARP undergoes automodification which promotes its disassociation from DNA and enables it to form a stable nucleoplasmic protein complex comprised of SUMO1, P1ASγ, NEMO (IKKγ), and ATM. ATM-mediated phosphorylation of NEMO triggers sumoylation of the inactive NF-κB complex in the cytoplasm and subsequent ubiquitination of NEMO from the activated complex. In the nucleus, PARP physically binds to the p65/p50 subunits through p300-CBP histone acetyltransferase, allowing NF-κB-driven transcription of proinflammatory molecules. Unsustainable levels of inflammatory gene expression can lead to reciprocal increases in DNA damage, causing a positive feedback loop that further activates PARP and NF-κB, exacerbating oxidative stress and neuroinflammation. ATM, ataxia–telangiectasia mutated; BER, base excision repair; NF-κB, nuclear factor κB; PARP, poly(ADP-ribose) polymerase; SSBs, single strand breaks.

Figure 3.

Differential impact of radiation exposure ± PARP inhibition in tumor and normal brain. (A) In tumor cells, PARP binds to DNA SSB in glioma cells and through the recruitment of BER proteins, facilitates DNA repair. (B) PARP inhibitors compete with NAD⁺ at the PARP catalytic domain causing inhibition of PARP catalytic activity and the accumulation of unrepaired SSBs. This leads to the formation of DSBs, increased genomic instability, and cell death. (C) In the normal brain, radiation-induced DNA damage and the associated increase in PARP hyperactivity through interaction with NF-κB results in neuroinflammation, leading to reciprocal DNA damage and neural cell death. Hyperactivation of PARP and neuroinflammation can also exacerbate PARP-dependent cell death through the nuclear transfer of AIF from mitochondria, leading to apoptotic cell death of neurogenic cells contributing to cognitive decline. (D) PARP inhibitors prevent PARP activation and PARP’s interaction with NF-κB, causing a reduction in the expression of inflammatory mediators and a reduction in neuroinflammation. Additionally, reduced PARP activation mitigates the onset of PARP-dependent cell death of neuronal cells. AIF, apoptosis-inducing factor; BER, base excision repair; DSBs, double strand breaks; NAD⁺, nicotinamide adenine dinucleotide; NF-κB, nuclear factor κB; PARP, poly(ADP-ribose) polymerase; SSBs, , single strand breaks.