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Desloratadine alleviates ALS-like pathology in hSOD1G93A mice via targeting 5HTR2A on activated spinal astrocytes

Acta Pharmacologica Sinica volume 45, pages 926–944 (2024)Cite this article

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive loss of motor neurons in the spinal cord, cerebral cortex and brain stem. ALS is characterized by gradual muscle atrophy and dyskinesia. The limited knowledge on the pathology of ALS has impeded the development of therapeutics for the disease. Previous studies have shown that autophagy and astrocyte-mediated neuroinflammation are involved in the pathogenesis of ALS, while 5HTR2A participates in the early stage of astrocyte activation, and 5HTR2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR2A antagonist, in human SOD1G93A (hSOD1G93A) ALS model mice, and elucidated the underlying mechanisms. HSOD1G93A mice were administered DLT (20 mg·kg−1·d−1, i.g.) from the age of 8 weeks for 10 weeks or until death. ALS onset time and lifespan were determined using rotarod and righting reflex tests, respectively. We found that astrocyte activation accompanying with serotonin receptor 2 A (5HTR2A) upregulation in the spinal cord was tightly associated with ALS-like pathology, which was effectively attenuated by DLT administration. We showed that DLT administration significantly delayed ALS symptom onset time, prolonged lifespan and ameliorated movement disorders, gastrocnemius injury and spinal motor neuronal loss in hSOD1G93A mice. Spinal cord-specific knockdown of 5HTR2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1G93A mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice. In summary, 5HTR2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease.

DLT as a 5HTR2A antagonist effectively promoted autophagy to reduce mutant hSOD1 level through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocytic neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice.

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Fig. 1: 5HTR2A was upregulated in the spinal astrocytes of hSOD1G93A mice and ALS patients.
Fig. 2: DLT delayed ALS onset time and ameliorated the dyskinesias of ALS mice through 5HTR2A.
Fig. 3: DLT protected against spinal motor neuronal damage in ALS mice through 5HTR2A.
Fig. 4: DLT promoted autophagy to clear spinal hSOD1G93A protein in ALS mice.
Fig. 5: DLT promoted autophagy to clear spinal hSOD1G93A protein through 5HTR2A/cAMP/AMPK pathway in ALS mice.
Fig. 6: DLT suppressed spinal oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway in ALS mice.
Fig. 7: DLT suppressed spinal astrocytic activation through 5HTR2A/cAMP/AMPK pathway in ALS mice.
Fig. 8: DLT suppressed spinal astrocytic NLRP3 inflammasome activation through 5HTR2A/cAMP/AMPK/NF-κB pathway in ALS mice.
Fig. 9: DLT repressed the crosstalk between spinal astrocytic neuroinflammation and neuronal damage through 5HTR2A.

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Data availability

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82273930), the National Natural Science Foundation for Young Scientists of China (82304468, 82304494, 82204486), Major Program of the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (23KJA350002), the Natural Science Foundation for Young Scientists of Nanjing University of Chinese Medicine (XPT82204486), Natural Science Foundation of Jiangsu Province (BK20200570).

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  1. These authors contributed equally: Jian Lu, An-xu He, Zhuo-ying Jin.

Authors and Affiliations

  1. Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Jian Lu, An-xu He, Zhuo-ying Jin, Meng Zhang, Fan Zhou, Lin Ma, Jia-ying Wang & Xu Shen

  2. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Zhong-xin Li & Hong-ming Jin

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Contributions

XS, JYW and JL designed the study. XS reviewed the manuscript. JL, ZYJ, AXH, MZ, ZXL, FZ and LM performed the animal and cell experiments. JL, ZYJ and AXH analyzed and interpreted data. JL wrote the manuscript. JL, XS, JYW and HMJ are the guarantors of this work and, as such, have full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the manuscript.

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Lu, J., He, Ax., Jin, Zy. et al. Desloratadine alleviates ALS-like pathology in hSOD1G93A mice via targeting 5HTR2A on activated spinal astrocytes. Acta Pharmacol Sin 45, 926–944 (2024). https://doi.org/10.1038/s41401-023-01223-2

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