Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease caused by loss of motor neurons. ALS patients experience rapid deterioration in muscle function with an average lifespan of 3–5 years after diagnosis. Currently, the most effective therapeutic only extends lifespan by a few months, thus highlighting the need for new and improved therapies. Neurotrophic factors (NTFs) are important for neuronal development, maintenance, and survival. NTF treatment has previously shown efficacy in pre-clinical ALS models. However, clinical trials using NTFs produced no major improvements in ALS patients, due in part to the limited blood brain barrier (BBB) penetration. In this study we assessed the potential neuroprotective effects of a novel class of compounds known as MicroNeurotrophins (MNTs). MNTs are derivatives of Dehydroepiandrosterone (DHEA), an endogenous neurosteroid that can cross the BBB and bind to tyrosine kinase receptors mimicking the pro-survival effects of NTFs. Here we sought to determine whether MNTs were neuroprotective in two different models of ALS. Our results demonstrate that BNN27 (10 μM) attenuated loss of motor neurons co-cultured with astrocytes derived from human ALS patients with SOD1 mutations via the reduction of oxidative stress. Additionally, in the G93A SOD1 mouse, BNN27 (10 mg/kg) treatment attenuated motor behavioral impairment in the paw grip endurance and rotarod tasks at postnatal day 95 in female but not male mice. In contrast, BNN27 (10 mg/kg and 50 mg/kg) treatment did not alter any other behavioral outcome or neuropathological marker in male or female mice. Lastly, BNN27 was not detected in post-mortem brain or spinal cord tissue of treated mice due to the rapid metabolism of BNN27 by mouse hepatocytes relative to human hepatocytes. Together, these findings demonstrate that BNN27 treatment failed to yield significant neuroprotective effects in the G93A SOD1 model likely due to its rapid rate of metabolism in mice.

Highlights

  • Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of motor neurons in the cortex, brainstem, and spinal cord

  • To determine which MNT to test in a mouse model of ALS, we assessed the effects of 3 MNTs, BNN20, BNN27, and BNN23, in human astrocytes derived from ALS patients with SOD1 mutations co-cultured with mouse motor neurons (MNs) in vitro

  • BNN27 (10 μM) significantly attenuated the motor neuron loss seen in untreated SOD1 iAstrocytes as shown by an increase in MN GFP signal (BNN20- 10 μM: 77.84%, SOD1 untreated: 47.60%; p

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Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of motor neurons in the cortex, brainstem, and spinal cord. The therapeutic effects of several NTFs were tested in clinical trials for ALS as well as other neurodegenerative disorders [23,24,25,26]. Despite the promising preclinical results in ALS models, NTFs have yet to meet their potential as therapies for the treatment of ALS as they did not demonstrate efficacy in clinical trials [27,28,29,30]. Subsequent studies demonstrated that most NTFs do not readily cross the blood-brain barrier (BBB) [31,32,33,34], highlighting a major obstacle underlying the lack of efficacy in NTF clinical trials [35]

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