Emerging neuroprotective interventions in periventricular leukomalacia - A systematic review of preclinical studies

ABSTRACT

Introduction

Periventricular leukomalacia (PVL) is a result of various antenatal, intrapartum, or postnatal insults to the developing brain and is an important harbinger of cerebral palsy in preterm neonates. There is no proven therapy for PVL. This calls for appraisal of targeted therapies that have been investigated in animal models to evaluate their relevance in a clinical research context.

Areas covered

This systematic review identifies interventions that were evaluated in preclinical studies for neuroprotective efficacy against PVL. We identified 142 studies evaluating various interventions in PVL animal models (search method is detailed in section 2).

Expert opinion

Interventions that have yielded significant results in preclinical research, and that have been evaluated in a limited number of clinical trials include stem cells, erythropoietin, and melatonin. Many other therapeutic modalities evaluated in preclinical studies have been identified, but more data on their neuroprotective potential in PVL must be garnered before they can be considered for clinical trials. Because most of the tested interventions had only a partial efficacy, a combination of interventions that could be synergistic should be investigated in future preclinical studies. Furthermore, since the nature and pattern of perinatal insults to preterm brain predisposing it to PVL are substantially variable, individualized approaches for the choice of appropriate neuroprotective interventions tailored to different subgroups of preterm neonates should be explored.

KEYWORDS:

• Periventricular leukomalacia
• preterm brain injury
• white matter
• therapy
• prevention
• neuroprotection
• preclinical studies
• animal models

Article Highlights

• Only a few interventions namely, stem cells, erythropoietin, and melatonin have been evaluated extensively in preclinical research and in a limited number of clinical trials for their neuroprotective efficacy against PVL.

• Many other therapeutic modalities have been evaluated in preclinical studies, but more data on their neuroprotective efficacy is necessary before they can be considered for clinical trials.

• The interventions tested in preclinical studies act through one or more of the five major mechanisms, namely anti-inflammatory, antioxidant, anti-apoptotic, anti-excitotoxic, and trophic/regenerative.

• The dosage regimens of most of the evaluated neuroprotective agents are highly variable across preclinical studies. The optimal dosage that confers maximal benefits (with the least adverse events) must be determined before they are translated for widespread clinical use in preterm neonates.

• There is a paucity of preclinical research on individualized approaches for the choice of appropriate neuroprotective interventions tailored to different subgroups of preterm neonates with varying etiopathogenesis/insults resulting in PVL.

• Future research should explore the long-term safety of stem cells, and the optimal timing of administration and dosage regimens of well-explored therapeutic interventions such as erythropoietin and melatonin.

• Among the less explored interventions, those that are already in clinical use for other indications and those with favorable safety profiles (such as thyroxine, ibuprofen, and inhaled nitric oxide) may be prioritized for further investigation of their neuroprotective efficacy in PVL

Contributor statement

Dr Thangaraj Abiramalatha conceptualized the systematic review. Mr Abdul Kareem Pullattayil devised the literature search strategy for the databases. Dr Thangaraj Abiramalatha, Dr Anand Kumar Ponnala and Dr Viraraghavan Vadakkencherry Ramaswamy performed literature search and data extraction. Dr Thangaraj Abiramalatha wrote the first draft of the manuscript. Dr Venkat Reddy Kallem designed all the infographics. Dr Viraraghavan Vadakkencherry Ramaswamy, Dr Venkat Reddy Kallem, Dr Yogeshkumar Murkunde, Dr Alan M Punnoose, Dr Aravindhan V and Dr Prakash Amboiram revised the initial draft. All authors approved the final version for submission and agree to be accountable for all aspects of the work.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This systematic review was conducted while performing another preclinical study funded by the Department of Biotechnology, Government of India. However, the authors of this systematic review did not receive any funding for conducting this review.