Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (5): 1890-1898.doi: 10.4103/NRR.NRR-D-24-01464

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Extracellular nucleotides mediate viral central nervous system infections: Key alarmins of neuroinflammation and neurodegeneration

Raíssa Leite-Aguiar1, 2, #, Elaine Paiva-Pereira1, 2, #, Robson Coutinho-Silva2 , Cláudia Pinto Figueiredo3 , Luiz Eduardo Baggio Savio1, 2, *   

  1. 1 Laboratório de Neuroimunologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;  2 Laboratório de Imunofisiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;  3 Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
  • Online:2026-05-15 Published:2025-08-21
  • Contact: Luiz Eduardo Baggio Savio, PhD, savio@biof.ufrj.br.
  • Supported by:
    This work was supported by funds from the Conselho Nacional de Desenvolvimento Científico e Tecnológico do Brasil (CNPq) (312286/2023-6; 307201/2023-6; and Instituto Nacional Saúde Cerebral INSC, No. 406020/2022-1); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro - FAPERJ (E-26/010.002260/2019, E-26/010.001652/2019, E-26/010.101036/2018, E-26/202.774/2018; E-26/210.240/2020; E-26/211.138/2021, 26/210.823/2021, E-26/211.325/2021, E-26/210.779/2021, E-26/201.086/2022; E-26/210.312/2022; E-26/203.262/2023; E-26/200.195/2023) (to LEBS).

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Abstract: Recent increases in infectious diseases affecting the central nervous system have raised concerns about their role in neuroinflammation and neurodegeneration. Viral pathogens or their products can invade the central nervous system and cause damage, leading to meningitis, encephalitis, meningoencephalitis, myelitis, or post-infectious demyelinating diseases. Although neuroinflammation initially has a protective function, chronic inflammation can contribute to the development of neurodegenerative diseases. Mechanisms such as protein aggregation and cellular disturbances are implicated with specific viruses such as herpes simplex virus type 1 and Epstein-Barr virus being associated with Alzheimer’s disease and multiple sclerosis, respectively. Extracellular nucleotides, particularly adenosine triphosphate and its metabolites are released from activated, infected, and dying cells, acting as alarmins mediating neuroinflammation and neurodegeneration. When viruses infect central nervous system cells, adenosine triphosphate is released as an alarmin, triggering inflammatory responses. This process is mediated by purinergic receptors, divided into two families: P1, which responds to adenosine, and P2, activated by adenosine triphosphate and other nucleotides. This review highlights how specific viruses, such as human immunodeficiency virus type 1, Theiler’s murine encephalomyelitis virus, herpes simplex virus type 1, Epstein-Barr virus, dengue virus, Zika virus, and severe acute respiratory syndrome coronavirus 2, can initiate inflammatory responses through the release of extracellular nucleotides, particularly adenosine triphosphate, which act as critical mediators in the progression of neuroinflammation and neurodegenerative disorders. A better understanding of purinergic signaling pathways in these diseases may suggest new potential therapeutic strategies for targeting neuroinflammation to mitigate the long-term consequences of viral infections in the central nervous system.

Key words: adenosine triphosphate, dengue, Epstein-Barr virus, herpes simplex virus type 1, human immunodeficiency virus type 1, neurodegenerative diseases, neurotropic infections, purinergic signaling, severe acute respiratory syndrome coronavirus 2, virus, Zika