Probing Caffeine Administration as a Medical Management for Hydrocephalus: An Experimental Study

Abstract

Background

Hydrocephalus is currently managed by cerebrospinal fluid diversion from the cerebral ventricles to other body sites, but this is complicated by obstruction and infection in young infants, thus adding to morbidity and mortality. Studies have reported caffeine to be a pleiotropic neuroprotective drug in the developing brain due to its antioxidant, anti-inflammatory, and antiapoptotic properties, with improved white matter microstructural development. In this study, we investigate the use of caffeine administration as a possible means of pharmacological management for hydrocephalus.

Methods

A total of 76 three-day-old mice pups from 10 dams were divided into four groups: hydrocephalus was induced in the pups in two groups by intracisternal injection of kaolin suspension, and their dams were given either caffeine (50 mg/kg by gavage) or water daily for 21 days; the dams in the other 2 (non-hydrocephalic) groups similarly had either caffeine or water; the pups received caffeine administered via lactation. Developmental neurobehavioral tests were performed until day 21, when the pups were sacrificed. Their brains were removed and processed for Cresyl and Golgi staining; both quantitative and qualitative analyses were then carried out.

Results

Improved developmental motor activities and reflexes were observed in the hydrocephalus + caffeine–treated pups. Caffeine administration was associated with reduced cell death and increased dendritic arborization of the neurons in the sensorimotor cortex and striatum of hydrocephalic mice pups.

Conclusion

Caffeine administration appears to have promise as an adjunct in hydrocephalus management, and its use needs to be further explored.

Introduction

Caffeine is an adenosine receptor antagonist, which binds to the adenosine receptors and blocks the actions of adenosine by competitive antagonism.¹ Adenosine functions as a neurotransmitter with receptors present in every cell type in the brain,² thus suggesting that caffeine can potentially affect all areas of the brain.³

Caffeine is usually a component of many beverages (coffee, tea, energy drinks), plants (cocoa beans, kola nuts), and drugs (appetite suppressants, analgesics)⁴ and a commonly prescribed drug in the current neonatal practice. The efficacy, tolerability, wide therapeutic index, and safety margin of caffeine have made it the drug of choice for apnea for prematurity.⁵

The effects of caffeine are biphasic and highly dependent on dose, prior exposure, and cognitive and physical state at the time of consumption.⁶ Studies in experimental animals have shown that exposure to caffeine during pregnancy and lactation may have deleterious effects on the developing brain, causing motility disabilities, sleep disorders, and behavioral abnormalities such as hyperactivity in the infant, hyperexcitable hippocampus, defective neuronal development, long-lasting cognitive deficits, decreased cerebellar weight, and increased saturated fatty acids in the cerebellum.7, 8, 9 Caffeine has, however, been used successfully as a drug of choice in the management of apnea of prematurity in very-low-birth-weight babies, and studies, including those with long-term follow-up, have been carried out to determine its efficacy and safety. Caffeine-treated infants were found to have improved neurodevelopmental, neurocognitive outcomes and reduced motor impairments when compared with placebo-treated ones at 1½, five, and 11 years posttreatment, respectively.¹⁰ Caffeine administration has also been found to be beneficial in several experimental neurological conditions. Caffeine decreases dopaminergic neuron loss in the substantia nigra following the injection of 1-methyl-4-phenylpyridinium into the cerebral ventricles in a rat model of progressive Parkinson disease.¹¹ Caffeine prevents neuronal loss in the cerebellum and the hippocampus following exposure to a high electromagnetic field of 900 MHz¹²; it also reversibly increases sharp waves in acute hippocampal slices in a dose-dependent manner, thus promoting memory consolidation.¹³

Hydrocephalus is a relatively common neurological condition especially in children, occurring in 0.5 to 1 per 1000 live births worldwide.¹⁴ The motor and cognitive deficits that occur in hydrocephalus are thought to be partly due to axonal damage within the periventricular white matter. In addition, myelin disruption is prominent in hydrocephalus,¹⁵ accounting for many of the neurological deficits observed. Stretching of the ependymal layer, thinning of the corpus callosum, extracellular edema, and reduced cortical thickness have been observed to correlate with the degree of hydrocephalus.¹⁶

Studies have reported the neuroprotective effects of caffeine in hypoxia ischemia, treatment of apnea in preterm babies, and blast-induced traumatic brain injury.17, 18, 19 Caffeine was found to reduce ventriculomegaly and protect the oligodendrocytes, hence preserving myelination in hypoxia-induced periventricular white matter injury,²⁰ and reduced cell death in different brain regions, thus protecting the neonatal mouse brain after hypoxia ischemia.²¹ Caffeine has been described as a pleiotropic neuroprotective drug in the developing brain due to its antioxidant, anti-inflammatory, and antiapoptotic properties.²² We therefore investigate the possible ameliorative effect of caffeine administration on the neurobehavioral and structural brain changes in neonatal mice with experimental hydrocephalus.