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Objective Prolonged human immunodeficiency virus-1 (HIV-1) infection leads to neurological debilitation, including motor dysfunction and frank dementia. Although pharmacological control of HIV infection is now possible, HIV-associated neurocognitive disorders (HAND) remain intractable. Here, we report that chronic treatment with erythropoietin (EPO) and insulin-like growth factor-I (IGF-I) protects against HIV/gp120-mediated neuronal damage in culture and in vivo.

Neutrophil emigration is mediated by adhesion proteins that are highly expressed on the endothelial surface during inflammatory processes in the brain. Intercellular adhesion molecule-1 (ICAM-1) is an inducible adhesion molecule that binds to leukocyte integrins and facilitates neutrophil adhesion and transendothelial migration. To study the role of ICAM-1 during ischemia and reperfusion in the brain, we analyzed the effect of transient focal cerebral ischemia in ICAM-1-deficient mice generated by gene targeting in embryonic stem cells. Transient focal ischemia was induced by occluding the left middle cerebral artery for 3 hours followed by a 21- or 45-hour reperfusion period. When compared with their wild-type littermates, ICAM-1-deficient mice were less susceptible to cerebral injury as demonstrated by a 5.6- or 7.8-fold reduction in infarction volume, respectively. These data support the premise that neutrophil adhesion in ischemic areas may be deleterious and that ICAM-1 deficiency reduces neurological damage after transient focal cerebral ischemia.

Prolonged human immunodeficiency virus-1 (HIV-1) infection leads to neurological debilitation, including motor dysfunction and frank dementia. Although pharmacological control of HIV infection is now possible, HIV-associated neurocognitive disorders (HAND) remain intractable. Here, we report that chronic treatment with erythropoietin (EPO) and insulin-like growth factor-I (IGF-I) protects against HIV/gp120-mediated neuronal damage in culture and in vivo.Initially, we tested the neuroprotective effects of various concentrations of EPO, IGF-I, or EPO+IGF-I from gp120-induced damage in vitro. To assess the chronic effects of EPO+IGF-I administration in vivo, we treated HIV/gp120-transgenic or wild-type mice transnasally once a week for 4 months and subsequently conducted immunohistochemical analyses.Low concentrations of EPO+IGF-I provided neuroprotection from gp120 in vitro in a synergistic fashion. In vivo, EPO+IGF-I treatment prevented gp120-mediated neuronal loss, but did not alter microgliosis or astrocytosis. Strikingly, in the brains of both humans with HAND and gp120-transgenic mice, we found evidence for hyperphosphorylated tau protein (paired helical filament-I tau), which has been associated with neuronal damage and loss. In the mouse brain following transnasal treatment with EPO+IGF-I, in addition to neuroprotection we observed increased phosphorylation/activation of Akt (protein kinase B) and increased phosphorylation/inhibition of glycogen synthase kinase (GSK)-3beta, dramatically decreasing downstream hyperphosphorylation of tau. These results indicate that the peptides affected their cognate signaling pathways within the brain parenchyma.Our findings suggest that chronic combination therapy with EPO+IGF-I provides neuroprotection in a mouse model of HAND, in part, through cooperative activation of phosphatidylinositol 3-kinase/Akt/GSK-3beta signaling. This combination peptide therapy should therefore be tested in humans with HAND.

Recent evidence in vitro has suggested that neuronal injury observed in the acquired immunodeficiency syndrome dementia complex may depend, at least in part, on toxic effects of the human immunodeficiency virus type 1 envelope protein, gp120. This laboratory previously reported that members of the dihydropyridine class of calcium channel antagonists, nimodipine and nifedipine, greatly attenuate the rise in intracellular calcium engendered by gp120 and prevent subsequent neuronal injury. The relatively low (nanomolar) concentrations of dihydropyridines that were effective suggested that their action might be exerted at the level of the L-type of voltage-dependent calcium channels. In the present study, I tested members of the three other major classes of Ca2+ channel antagonist drugs to determine if they too could prevent neurotoxicity induced by gp120. At the maximal dose that did not cause neuronal damage in and of itself, a diphenylalkylamine piperazine derivative (flunarizine, 10 microM) was the most effective, a phenylalkylamine (verapamil, 100 microM) was possibly effective, whereas a benzothiazepine (diltiazem, 1 microM) was ineffectual in protecting rat retinal ganglion cells from gp120-induced toxicity in vitro. To explain these results, previous work has shown that the various classes of Ca2+ channel antagonists may exhibit differential potency in blocking voltage-dependent Ca2+ current in neurons, with dihydropyridines and flunarizine being the most potent at neuronal calcium channels. Moreover, these channels on mammalian central neurons are relatively insensitive to agents such as verapamil and diltiazem compared with other cell types like muscle. The low micromolar concentrations necessary for potency of flunarizine is in keeping with that predicted by binding and electrophysiological studies for block of voltage-dependent calcium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Increasing evidence supports the hypothesis that escalating levels of excitatory amino acids (EAAs) are responsible for neuronal cell death in a variety of acute neurological conditions including hypoxia/ischemia, trauma, seizures, and hypoglycemia. EAAs may also contribute to several chronic neurodegenerative diseases including Huntington's disease, parkinsonism, and acquired immunodeficiency syndrome dementia. A predominant form of neurotoxicity appears to be mediated by excessive activation of the N-methyl-D-aspartate subtype of glutamate receptor. This laboratory recently reported that memantine, an antiparkinsonian drug, is a potent N-methyl-D-aspartate antagonist capable of preventing the death of central neurons both in vitro and in vivo when given coincident to an EAA insult. In the present study, we found that 12 microM memantine prevented the death of neonatal rat retinal ganglion cells in primary culture when administered up to 4 hours after the initiation of N-methyl-D-aspartate receptor-mediated neurotoxicity.