Background:  HIV-1-associated cognitive impairments are associated with a profound encephalopathy fueled by virus-infected and immune activated mononuclear phagocytes (MP; perivascular blood borne macrophages and microglia). CEP-1347, an anti-apoptotic kinase inhibitor, has neuroprotective activities in models of Parkinson’s disease and other models of neurodegenerative diseases, and induces broad anti-inflammatory activities due to its inhibitory effects on mixed lineage kinases. Based on these observations, we assessed the anti-inflammatory and neuroprotective properties of CEP-1347 in a murine model of HIV-1 encephalitis (HIVE).

Methods:  HIV-1 _ADA infected human monocyte-derived macrophages (MDM) were treated with CEP-1347. Cell viability and viral replication were measured. Pharmacokinetic studies were performed on CB17 severe combined immune deficient (SCID) and C57Bl mice at serial CEP-1347 dosages of 1.5 to 15 mg/kg. SCID mice were stereotactically injected with HIV-1_ADA infected MDM into the basal ganglia to assess drug effects. Groups of 5 animals were injected intraperitoneally daily with 0.5 to 15 mg/kg CEP-1347 for 7 days, then sacrificed and brains extracted for immunocytochemical, and reverse transcriptase polymerase chain reaction (RT-PCR) tests.

Results:  No MDM toxicity by CEP-1347 was demonstrated. Treatment in vivo with Cep-1347 was associated with a significant reduction in microgliosis by Iba-1 (p <0.001) and with protection against neuronal loss and dendritic damage, as assessed by immunohistochemical staining for MAP2 (p <0.05), NeuN (p <0.05), and phosphorylated neurofilament (p <0.001). P values were generated for comparisons between drug-treated and untreated control animals. Effects on viral replication are being assessed.

Conclusions:  CEP-1347 is both anti-inflammatory and neuroprotective in murine HIV encephalopathy and as such warrants further study as an adjunctive therapy for human disease.