Potential role of Plasmodium falciparum-derived ammonia in the pathogenesis of cerebral malaria.

Sammy Kimoloi,Khalid Rashid

doi:10.3389/fnins.2015.00234

Abstract

Cerebral malaria (CM) is the most severe complication associated with Plasmodium falciparum infection. The exact pathogenic mechanisms leading to the development of CM remains poorly understood while the mortality rates remain high. Several potential mechanisms including mechanical obstruction of brain microvasculature, inflammation, oxidative stress, cerebral energy defects, and hemostatic dysfunction have been suggested to play a role in CM pathogenesis. However, these proposed mechanisms, even when considered together, do not fully explain the pathogenesis and clinicopathological features of human CM. This necessitates consideration of alternative pathogenic mechanisms. P. falciparum generates substantial amounts of ammonia as a catabolic by-product, but lacks detoxification mechanisms. Whether this parasite-derived ammonia plays a pathogenic role in CM is presently unknown, despite its potential to cause localized brain ammonia elevation and subsequent neurotoxic effects. This article therefore, explores and proposes a potential role of parasite-derived ammonia in the pathogenesis and neuropathology of CM. A consideration of parasite-derived ammonia as a factor in CM pathogenesis provides plausible explanations of the various features observed in CM patients including how a largely intravascular parasite can cause neuronal dysfunction. It also provides a framework for rational development and testing of novel drugs targeting the parasite's ammonia handling.

Highlights

Cerebral malaria (CM) is one of the most common and fatal complications associated with Plasmodium falciparum infection (Newton et al, 2000)
Experimental cerebral malaria (ECM) in murine models has revealed metabolic changes that point toward parasite-induced perturbation of ammonia detoxification (Ghosh et al, 2012)
It is conceivable that sequestered parasites in the brain vasculature known to produce large amounts of ammonia as a catabolic by-product, may disrupt normal brain ammonia metabolism leading to local accumulation of ammonia

Summary

Introduction

Cerebral malaria (CM) is one of the most common and fatal complications associated with Plasmodium falciparum infection (Newton et al, 2000). Despite the availability of effective antimalarial drugs, CM mortality rates in malaria afflicted regions remain high, ranging between 15 and 20% (Mishra and Newton, 2009). This has partly been attributed to the fact that a number of patients succumb to CM before the onset of administered anti-malarial therapeutic effects (Mishra and Newton, 2009). Transient and persistent neurocognitive impairments are common among cerebral malaria survivors, mostly children (van der Wal et al, 2005; Idro et al, 2010). Several mechanisms have been hypothesized to play a role in the pathogenesis of CM including; mechanical obstruction of brain microvasculature by sequestered parasitized red blood cells (PRBCs), inflammation, hemostatic dysfunction, excessive parasite-derived lactate, and oxidative stress (Berendt et al, 1994; Medana et al, 2001; van der Heyde et al, 2006; Mariga et al, 2014)

The ammonia hypothesis of cerebral malaria

Human Brain Ammonia Uptake and Metabolism

Elevated Brain Ammonia Hypothesis

Findings

Conclusion