Repurposing azithromycin for neuroprotection in neonates

In this issue of Pediatric Research, Barks and his colleagues from the University of Michigan tested the effectiveness of intraperitoneal (i.p.) azithromycin as an anti-inflammatory post-injury (rescue) neuroprotectant in the P7 (near-term equivalent) and P10 (term equivalent) rat model of neonatal hypoxia–ischemia (HI) brain injury using the Vannucci model. Based on their experimental results, Barks et al. concluded that a 3-dose regimen of azithromycin delayed to 2 h after the HI insult and continued for 2 more doses (24 hours apart) was superior than control (normal saline) or single dose. Azithromycin affords protection against: (i) sensorimotor deficits and (ii) cortical, striatal, and hippocampal injury (P7 model) or cortical injury (P10 model) at P35. The efficacy of azithromycin was dose dependent and the neuroprotection was lost if therapy was delayed further than 2 h after the HI insult.¹ This is a well-designed and extremely timely paper, discussing once again the effectiveness of repurposed medications in an attempt to provide neuroprotection following perinatal brain injury. The strategy of repurposing available medications for new indications speeds the translation from bench to bedside.^2,3 One of the putative mechanisms of action of azithromycin likely includes the drug-induced polarization of macrophages toward M2 phenotype, limiting blood–brain barrier damage and resulting in decreased infiltration of neurotrophils and mononuclear cells to the brain, as speculated from the stroke model of transient middle cerebral artery occlusion and i.p. azithromycin treatment by Amantea et al.⁴ Neuroprotection linked to the treatment with azithromycin is also reported in models of retinal ischemic injury in rats.⁵ Thus, azithromycin (and other macrolides) appears to provide neuroprotection against ischemic, hypoxic–ischemic, and ischemic–reperfusion brain injuries in models of preconditioning and post-injury treatment as shown by Barks et al. and others.^1,4,6,7

The molecular pathway targeted by azithromycin to provide neuroprotection to the developing brain remains elusive and it is not the focus of this paper by Barks and colleagues. However, azithromycin appears to limit the translocation of nuclear factor (NF)-κB and activator protein (AP)-1 to the nucleus, known transcription factors for pro-inflammatory cytokine expression, resulting in their downregulation in glial cells in a poly [ADP-ribose] polymerase (PARP)-1-independent manner.⁸ Since the PARP-1-mediated molecular pathway preferentially produces necrotic-like cell death after neonatal HI injury in males mice,^9,10,11 the lack of PARP-1 dependence in the mechanism of action of azithromycin could explain the lack of sexual dimorphism reported by Barks et al.¹ Another mechanistic aspect not addressed is the effects of the known cardioprotection provided by azithromycin in models of myocardial infarction.¹² The effect of the improved cerebral perfusion resulting from improved cardiac output may account for some of the neuroprotection reported by Barks et al.¹.

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