Histamine Is an Inducer of the Heat Shock Response in SOD1-G93A Models of ALS

• Published in: International journal of molecular sciences 2019-08, Vol.20 (15), p.3793
• Main Authors: Apolloni, Savina, Caputi, Francesca, Pignataro, Annabella, Amadio, Susanna, Fabbrizio, Paola, Ammassari-Teule, Martine, Volonté, Cinzia
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Astrocytes - drug effects; Astrocytes - pathology; Autophagy; Bcl-2 protein; Bcl-x protein; Body weight; Cell culture; Cell Death - drug effects; Cytotoxicity; dendritic spines; Dendritic Spines - drug effects; Dendritic Spines - genetics; Disease; Disease Models, Animal; Drug dosages; Heat shock; heat shock proteins; Heat-Shock Response - drug effects; Heat-Shock Response - genetics; Histamine; Histamine - pharmacology; Histidine; Humans; Inflammation; Inspection; Mice; Microglia; Microglia - metabolism; Microglia - pathology; Motor neurons; Motor Neurons - drug effects; Motor Neurons - pathology; Mutation; Neurodegeneration; Neuroglia - drug effects; Neuroglia - pathology; Neuromuscular diseases; Neurons; Pathogenesis; Proteins; SOD1-G93A; Spinal cord; Spinal Cord - drug effects; Spinal Cord - pathology; Superoxide dismutase; Superoxide Dismutase-1 - genetics
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20153793

(1) Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial non-cell autonomous disease where activation of microglia and astrocytes largely contributes to motor neurons death. Heat shock proteins have been demonstrated to promote neuronal survival and exert a strong anti-inflammatory action in glia. Having previously shown that the pharmacological increase of the histamine content in the central nervous system (CNS) of SOD1-G93A mice decreases neuroinflammation, reduces motor neuron death, and increases mice life span, here we examined whether this effect could be mediated by an enhancement of the heat shock response. (2) Methods: Heat shock protein expression was analyzed in vitro and in vivo. Histamine was provided to primary microglia and NSC-34 motor neurons expressing the SOD1-G93A mutation. The brain permeable histamine precursor histidine was chronically administered to symptomatic SOD1-G93A mice. Spine density was measured by Golgi-staining in motor cortex of histidine-treated SOD1-G93A mice. (3) Results: We demonstrate that histamine activates the heat shock response in cultured SOD1-G93A microglia and motor neurons. In SOD1-G93A mice, histidine augments the protein content of GRP78 and Hsp70 in spinal cord and cortex, where the treatment also rescues type I motor neuron dendritic spine loss. (4) Conclusion: Besides the established histaminergic neuroprotective and anti-inflammatory effects, the induction of the heat shock response in the SOD1-G93A model by histamine confirms the importance of this pathway in the search for successful therapeutic solutions to treat ALS.