title: MicroNeurotrophins Improve Survival in Motor Neuron-Astrocyte Co-Cultures but Do Not Improve Disease Phenotypes in a Mutant SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.
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.
authors.affiliation: NeuroEpigenetics Laboratory, MassGeneral Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital, Boston, MA, 02129-4404, United States of America.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Glajch
authors.affiliation: Sheffield Institute of Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferraiuolo
authors.affiliation: NeuroEpigenetics Laboratory, MassGeneral Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital, Boston, MA, 02129-4404, United States of America.
authors.forename: Kaly A
authors.initials: KA
authors.lastname: Mueller
authors.affiliation: Sheffield Institute of Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Stopford
authors.affiliation: NeuroEpigenetics Laboratory, MassGeneral Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital, Boston, MA, 02129-4404, United States of America.
authors.forename: Varsha
authors.initials: V
authors.lastname: Prabhkar
authors.affiliation: Department of Pharmacology, School of Medicine, University of Crete, Institute of Molecular Biology & Biotechnology-FORTH, Heraklion 71003, Greece.
authors.forename: Achille
authors.initials: A
authors.lastname: Gravanis
authors.affiliation: Sheffield Institute of Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, United Kingdom.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: NeuroEpigenetics Laboratory, MassGeneral Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital, Boston, MA, 02129-4404, United States of America.
authors.forename: Ghazaleh
authors.identifier: http://orcid.org/0000-0003-3435-3544
authors.initials: G
authors.lastname: Sadri-Vakili
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D018920:Coculture Techniques / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics; D009046:Motor Neurons / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010641:Phenotype; D013116:Spinal Cord / Q000187:drug effects; D000072105:Superoxide Dismutase-1 / Q000235:genetics*
chemical_list: D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1