The glial response to intracerebrally delivered therapies for neurodegenerative disorders: is this a critical issue?

Francesca Cicchetti,Roger A Barker

doi:10.3389/fphar.2014.00139

Abstract

The role of glial cells in the pathogenesis of many neurodegenerative conditions of the central nervous system (CNS) is now well established (as is discussed in other reviews in this special issue of Frontiers in Neuropharmacology). What is less clear is whether there are changes in these same cells in terms of their behavior and function in response to invasive experimental therapeutic interventions for these diseases. This has, and will continue to become more of an issue as we enter a new era of novel treatments which require the agent to be directly placed/infused into the CNS such as deep brain stimulation (DBS), cell transplants, gene therapies and growth factor infusions. To date, all of these treatments have produced variable outcomes and the reasons for this have been widely debated but the host astrocytic and/or microglial response induced by such invasively delivered agents has not been discussed in any detail. In this review, we have attempted to summarize the limited published data on this, in particular we discuss the small number of human post-mortem studies reported in this field. By so doing, we hope to provide a better description and understanding of the extent and nature of both the astrocytic and microglial response, which in turn could lead to modifications in the way these therapeutic interventions are delivered.

Highlights

Over the last 30 years, there has been a burgeoning of new therapeutic approaches to treat chronic neurodegenerative conditions of the central nervous system (CNS)
These approaches have essentially been of two main types: (i) Better symptomatic agents most notably deep brain stimulation (DBS) for Parkinson’s Disease (PD) as well as gene therapy approaches (e.g., AAV2-GAD; ProSavin®; hAADC gene therapy)
In the single post-mortem case looking at intra-parenchymal Glial cell line derived neurotrophic factor (GDNF) delivery in a patient with PD, there was evidence of host tyrosine hydroxylase (TH) fiber sprouting around the catheter tip with a low grade astrocytic, microglial and T-cell response (Love et al, 2005)

Summary

Introduction

Over the last 30 years, there has been a burgeoning of new therapeutic approaches to treat chronic neurodegenerative conditions of the central nervous system (CNS). DBS electrodes will induce an astrocytic and microglial response (Figure 1.1) the extent to which this adversely affects their efficacy in patients is unproven.

Results

Conclusion