Intranasal Delivery of Nerve Growth Factor in Neurodegenerative Diseases and Neurotrauma.

Luigi Manni,Giorgio Conti,Marzia Soligo,Antonio Chiaretti

doi:10.3389/fphar.2021.754502

Abstract

Since the 1980s, the development of a pharmacology based on nerve growth factor (NGF) has been postulated for the therapy of Alzheimer’s disease (AD). This hypothesis was based on the rescuing effect of the neurotrophin on the cholinergic phenotype of the basal forebrain neurons, primarily compromised during the development of AD. Subsequently, the use of NGF was put forward to treat a broader spectrum of neurological conditions affecting the central nervous system, such as Parkinson’s disease, degenerative retinopathies, severe brain traumas and neurodevelopmental dysfunctions. While supported by solid rational assumptions, the progress of a pharmacology founded on these hypotheses has been hampered by the difficulty of conveying NGF towards the brain parenchyma without resorting to invasive and risky delivery methods. At the end of the last century, it was shown that NGF administered intranasally to the olfactory epithelium was able to spread into the brain parenchyma. Notably, after such delivery, pharmacologically relevant concentration of exogenous NGF was found in brain areas located at considerable distances from the injection site along the rostral-caudal axis. These observations paved the way for preclinical characterization and clinical trials on the efficacy of intranasal NGF for the treatment of neurodegenerative diseases and of the consequences of brain trauma. In this review, a summary of the preclinical and clinical studies published to date will be attempted, as well as a discussion about the mechanisms underlying the efficacy and the possible development of the pharmacology based on intranasal conveyance of NGF to the brain.

Highlights

The physiological peculiarity of the nerve growth factor (NGF) to regulate the survival and phenotype maintenance of specific neuronal populations in the peripheral and central nervous system (PNS and CNS, respectively) has laid the foundation for a broad line of preclinical and clinical research, aimed at exploring its pharmacological potential for the treatment of neurodegenerative diseases and of the outcomes of neurotrauma (Aloe et al, 2012; Allen et al, 2013)
The pharmacology of iodinated NGF (IN-NGF) seems to be heading towards promising development, based on the ease of administration, the efficiency of drug distribution to the brain parenchyma and the efficacy demonstrated in a number of preclinical studies
In addition to those already discussed, deserve to be deepened, such as the role of exogenous NGF in modifying the proNGF/NGF ratio in the brain, the possible synergistic effects of other therapies to be associated with IN-NGF, the potential development of side effects and the development of proper IN delivery devices/strategies

Summary

INTRODUCTION

The physiological peculiarity of the nerve growth factor (NGF) to regulate the survival and phenotype maintenance of specific neuronal populations in the peripheral and central nervous system (PNS and CNS, respectively) has laid the foundation for a broad line of preclinical and clinical research, aimed at exploring its pharmacological potential for the treatment of neurodegenerative diseases and of the outcomes of neurotrauma (Aloe et al, 2012; Allen et al, 2013). The enormous amount of preclinical research, conducted on a large number of in vitro and in vivo models, has indicated Alzheimer’s disease (AD) as a primary field of intervention (Cattaneo et al, 2008; Cattaneo and Calissano, 2012). The rationale for this therapeutic approach stems from the selective effect of

Intranasal Nerve Growth Factor

Intraparenchymal and Intracerebroventricular Delivery of NGF to the Human Brain

Intranasal Delivery of Nerve Growth Factor to the Brain

Findings

DISCUSSION