Combination antiretroviral therapy (CART) has proven to effectively suppress systemic HIV burden, however, poor penetration into the central nervous system (CNS) provides incomplete protection. Although the severity of HIV-associated neurocognitive disorders (HAND) has been reduced, neurological disease is expected to exert an increasing burden as HIV-infected patients live longer. Strategies to enhance penetration of antiretroviral compounds into the CNS could help to control HIV replication in this reservoir but also carries an increased risk of neurotoxicity. Efforts to target antiretroviral compounds to the CNS will have to balance these risks against the potential gain. Unfortunately, little information is available on the actions of antiretroviral compounds in the CNS, particularly at concentrations that provide effective virus suppression. The current studies evaluated the direct effects of 15 anti-retroviral compounds on neurons to begin to provide basic neurotoxicity data that will serve as a foundation for the development of dosing and drug selection guidelines. Using sensitive indices of neural damage, we found a wide range of toxicities, with median toxic concentrations ranging from 2 to 10,000 ng/ml. Some toxic concentrations overlapped concentrations currently seen in the CSF but the level of toxicity was generally modest at clinically relevant concentrations. Highest neurotoxicities were associated with abacavir, efavarenz, etravirine, nevaripine, and atazanavir, while the lowest were with darunavir, emtracitabine, tenofovir, and maraviroc. No additive effects were seen with combinations used clinically. These data provide initial evidence useful for the development of treatment strategies that might reduce the risk of antiretroviral neurotoxicity.

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The strong repair and pro-survival functions of neurotrophins at their primary receptors, TrkA, TrkB and TrkC, have made them attractive candidates for treatment of nervous system injury and disease. However, difficulties with the clinical implementation of neurotrophin therapies have prompted the search for treatments that are stable, easier to deliver and allow more precise regulation of neurotrophin actions. Recently, the p75 neurotrophin receptor (p75NTR) has emerged as a potential target for pharmacological control of neurotrophin activity, supported in part by studies demonstrating 1) regulation of neural plasticity in the mature nervous system, 2) promotion of adult neurogenesis and 3) increased expression in neurons, macrophages, microglia, astrocytes and/or Schwann cells in response to injury and neurodegenerative diseases. Although the receptor has no intrinsic catalytic activity it interacts with and modulates the function of TrkA, TrkB, and TrkC, as well as sortilin and the Nogo receptor. This provides substantial cellular and molecular diversity for regulation of neuron survival, neurogenesis, immune responses and processes that support neural function. Upregulation of the p75NTR under pathological conditions places the receptor in a key position to control numerous processes necessary for nervous system recovery. Support for this possibility has come from recent studies showing that small, non-peptide p75NTR ligands can selectively modify pro-survival and repair functions. While a great deal remains to be discovered about the wide ranging functions of the p75NTR, studies summarized in this review highlight the immense potential for development of novel neuroprotective and neurorestorative therapies.

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Although several recent anatomical and physiological studies indicate that glutamate receptors are likely to play a role in the regulation of various hypothalamic functions, no attempt has yet been made to specifically characterize glutamate receptor densities, subtypes, or localization in the hypothalamus. To provide this basic information, we have characterized and mapped the binding of [3H]glutamate to N-methyl-D-aspartate (NMDA), non-NMDA, and metabotropic glutamate receptors throughout the diencephalon. Membrane binding assays revealed a [3H]glutamate binding density of 2.6 pmol/mg protein, approximately one third of the hippocampal density. Binding of subtype-specific agonists and antagonists was complex, but clearly indicated that each major glutamate subtype is present in all hypothalamic and preoptic regions in the following approximate relative densities: NMDA > metabotropic Glu receptor > kainate > or = alpha-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid. Receptor autoradiography confirmed the widespread presence of all major glutamate receptor subtypes with roughly the following relative regional densities: ventromedial, dorsomedial > paraventricular, anterior hypothalamic, supraoptic > arcuate, suprachiasmatic, lateral hypothalamic > preoptic area >> pituitary neural lobe, white matter > pituitary anterior lobe (negligible). Subtype expression varied regionally, with rostral hypothalamic and preoptic regions having proportionally higher levels of non-NMDA vs. NMDA binding. High densities of glutamate receptors in ventromedial and medial hypothalamic regions suggest a prominent role in neuroendocrine and autonomic regulation.