Neuroprotective activities of CEP-1347 in models of neuroAIDS

Dawn Eggert, Prasanta K. Dash, Santhi Gorantla, Huanyu Dou, Giovanni Schifitto, Sanjay B. Maggirwar, Stephen Dewhurst, Larisa Y Poluektova, Harris A. Gelbard, Howard Eliot Gendelman

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

When the nervous system is infected with HIV-1, it commonly results in neuroinflammation leading to overt neuronal dysfunction and subsequent cognitive and behavioral impairments. The multifaceted disease process, now referred to as HIV-1-associated neurocognitive disorders (HAND), provides a range of molecular targets for adjunctive therapies. One is CEP-1347, an inhibitor of mixed lineage kinases that elicits neuroprotective and anti-inflammatory responses in models of neurodegenerative diseases. Since HAND is associated with inflammatory encephalopathy induced by virus infection and mononuclear phagocytes (perivascular macrophages and microglia) immune activation, we investigated whether CEP-1347 could ameliorate disease in laboratory models of HAND. We now demonstrate that CEP-1347 reduces the levels of secreted proinflammatory cytokines and chemokines in HIV-1-infected human macrophages and attenuates dose-dependent neurotoxicity in rodent cortical neurons. CEP-1347-treated mice readily achieve therapeutic drug levels in peripheral blood. HIV-1 encephalitis (HIVE) mice, where human virus-infected monocyte-derived macrophages are stereotactically injected into the basal ganglia of CB17 severe combined immunodeficient mice, received daily intraperitoneal injections of CEP-1347. Here, CEP-1347 treatment of HIVE mice showed a dose-dependent reduction in microgliosis. Dendritic integrity and neuronal loss were sustained and prevented, respectively. These results demonstrate that CEP-1347 elicits anti-inflammatory and neuroprotective responses in an HIVE model of human disease and as such warrants further study as an adjunctive therapy for human disease.

Original languageEnglish (US)
Pages (from-to)746-756
Number of pages11
JournalJournal of Immunology
Volume184
Issue number2
DOIs
StatePublished - Jan 15 2010

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HIV-1
Encephalitis
Macrophages
Anti-Inflammatory Agents
SCID Mice
3,9-bis((ethylthio)methyl)-K-252a
Neuroaid
Microglia
Brain Diseases
Virus Diseases
Therapeutics
Phagocytes
Basal Ganglia
Intraperitoneal Injections
Chemokines
Neurodegenerative Diseases
Nervous System
Rodentia
Phosphotransferases
Cytokines

ASJC Scopus subject areas

  • Immunology

Cite this

Neuroprotective activities of CEP-1347 in models of neuroAIDS. / Eggert, Dawn; Dash, Prasanta K.; Gorantla, Santhi; Dou, Huanyu; Schifitto, Giovanni; Maggirwar, Sanjay B.; Dewhurst, Stephen; Poluektova, Larisa Y; Gelbard, Harris A.; Gendelman, Howard Eliot.

In: Journal of Immunology, Vol. 184, No. 2, 15.01.2010, p. 746-756.

Research output: Contribution to journalArticle

Eggert, D, Dash, PK, Gorantla, S, Dou, H, Schifitto, G, Maggirwar, SB, Dewhurst, S, Poluektova, LY, Gelbard, HA & Gendelman, HE 2010, 'Neuroprotective activities of CEP-1347 in models of neuroAIDS', Journal of Immunology, vol. 184, no. 2, pp. 746-756. https://doi.org/10.4049/jimmunol.0902962
Eggert D, Dash PK, Gorantla S, Dou H, Schifitto G, Maggirwar SB et al. Neuroprotective activities of CEP-1347 in models of neuroAIDS. Journal of Immunology. 2010 Jan 15;184(2):746-756. https://doi.org/10.4049/jimmunol.0902962
Eggert, Dawn ; Dash, Prasanta K. ; Gorantla, Santhi ; Dou, Huanyu ; Schifitto, Giovanni ; Maggirwar, Sanjay B. ; Dewhurst, Stephen ; Poluektova, Larisa Y ; Gelbard, Harris A. ; Gendelman, Howard Eliot. / Neuroprotective activities of CEP-1347 in models of neuroAIDS. In: Journal of Immunology. 2010 ; Vol. 184, No. 2. pp. 746-756.
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