Neuroprotective activities of CEP-1347 in models of neuroAIDS.
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.
Eggert
Dawn
D
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Dash
Prasanta K
PK
Gorantla
Santhi
S
Dou
Huanyu
H
Schifitto
Giovanni
G
Maggirwar
Sanjay B
SB
Dewhurst
Stephen
S
Poluektova
Larisa
L
Gelbard
Harris A
HA
Gendelman
Howard E
HE
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000517:prevention & control; D000818:Animals; D001479:Basal Ganglia / Q000821:virology; D002227:Carbazoles / Q000008:administration & dosage* / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D016207:Cytokines / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005911:Gliosis / Q000517:prevention & control; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D051379:Mice; D009474:Neurons / Q000821:virology; D018696:Neuroprotective Agents / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome
D002227:Carbazoles; D016207:Cytokines; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; C106592:3,9-bis((ethylthio)methyl)-K-252a