Traumatic spinal cord injury often results in complete loss of voluntary motor and sensory function below the site of injury. The long-term neurological deficits after spinal cord trauma may be due in part to widespread apoptosis of neurons and oligodendroglia in regions distant from and relatively unaffected by the initial injury. The caspase family of cysteine proteases regulates the execution of the mammalian apoptotic cell death program. Caspase-3 cleaves several essential downstream substrates involved in the expression of the apoptotic phenotype in vitro, including gelsolin, PAK2, fodrin, nuclear lamins and the inhibitory subunit of DNA fragmentation factor. Caspase-3 activation in vitro can be triggered by upstream events, leading to the release of cytochrome c from the mitochondria and the subsequent transactivation of procaspase-9 by Apaf-1. We report here that these upstream and downstream components of the caspase-3 apoptotic pathway are activated after traumatic spinal cord injury in rats, and occur early in neurons in the injury site and hours to days later in oligodendroglia adjacent to and distant from the injury site. Given these findings, targeting the upstream events of the caspase-3 cascade has therapeutic potential in the treatment of acute traumatic injury to the spinal cord.

Recent evidence suggests that injection drug users who abuse heroin are at increased risk for CNS complications from human immunodeficiency virus (HIV) infection. Opiate drugs may intrinsically alter the pathogenesis of HIV by directly modulating immune function and by directly modifying the CNS response to HIV. Despite this, the mechanisms by which opiates increase the neuropathogenesis of HIV are uncertain. Herein we describe the effect of morphine and the HIV-1 protein toxin Tat 1-72 on astroglial function in cultures derived from ICR mice. Astroglia maintain the blood brain barrier and influence inflammatory signaling in the CNS. Astrocytes can express μ opioid receptors, and are likely targets for abused opiates, which preferentially activate μ-opioid receptors. While Tat alone disrupts astrocyte function, when combined with morphine, Tat causes synergistic increases in [Ca 2+ ] i. . Moreover, astrocyte cultures treated with morphine and Tat showed exaggerated increases in chemokine release including monocyte chemoattractant protein-1 (MCP-1) and regulated on activation, normal T cell expressed and secreted (RANTES), as well as interleukin-6 (IL-6). Morphine-Tat interactions were prevented by the μ-opioid receptor antagonist β-funaltrexamine, or by immunoneutralizing Tat 1-72 or substituting a non-toxic, deletion mutant (Tat Δ31-61 ). Our findings suggest that opiates may increase the vulnerability of the CNS to viral entry (via recruitment of monocytes/macrophages) and ensuing HIV encephalitis by synergistically increasing MCP-1 and RANTES release by astrocytes. The results further suggest ‡ Abbreviations: alpha chemokine receptor (CXCR); beta chemokine ligand (CCL); beta chemokine receptor (CCR); β-funaltrexamine (β-FNA); calcium-induced calcium release (CICR); excitatory amino acid transporter-2 (EAAT2); granulocyte macrophage colony stimulating factor (GM-CSF); granulocyte-colony stimulating factor (G-CSF); human immunodeficiency virus (HIV); human immunodeficiency virus encephalitis (HIVE); inositol trisphosphate (IP 3 ); interferon (IFN); interleukin (IL); intracellular Ca 2+ ([Ca 2+ ] i ); monocyte chemoattractant protein (MCP); nor-binaltorphimine (nor-BNI); phosphatidylinositol 3-kinase (PI3-kinase); phospholipase C-γ (PLCγ); regulated on activation, normal T cell expressed and secreted (RANTES); soluble TNF receptor subunit (sTNFR1); stem cell factor (SCF); thrombopoietin (TPO); transactivator of transcription (Tat); tumor necrosis factor-α (TNF-α); vascular endothelial growth factor (VEGF).

Human immunodeficiency virus-1 (HIV-1) infection affects the striatum resulting in gliosis and neuronal losses. To determine whether HIV-1 proteins induce striatal neurotoxicity through an apoptotic mechanism, mouse striatal neurons isolated on embryonic day 15 and the effects of HIV-1 Tat 1-72 and gp120 on survival were assessed in vitro.

Dynorphins, endogenous opioid neuropeptides derived from the prodynorphin gene, are involved in a variety of normative physiologic functions including antinociception and neuroendocrine signaling, and may be protective to neurons and oligodendroglia via their opioid receptor-mediated effects. However, under experimental or pathophysiological conditions in which dynorphin levels are substantially elevated, these peptides are excitotoxic largely through actions at glutamate receptors. Because the excitotoxic actions of dynorphins require supraphysiological concentrations or prolonged tissue exposure, there has likely been little evolutionary pressure to ameliorate the maladaptive, non-opioid receptor mediated consequences of dynorphins. Thus, dynorphins can have protective and/or proapoptotic actions in neurons and glia, and the net effect may depend upon the distribution of receptors in a particular region and the amount of dynorphin released. Increased prodynorphin gene expression is observed in several disease states and disruptions in dynorphin processing can accompany pathophysiological situations. Aberrant processing may contribute to the net negative effects of dysregulated dynorphin production by tilting the balance towards dynorphin derivatives that are toxic to neurons and/or oligodendroglia. Evidence outlined in this review suggests that a variety of CNS pathologies alter dynorphin biogenesis. Such alterations are likely maladaptive and contribute to secondary injury and the pathogenesis of disease.

Opiate abuse alters the progression of human immunodeficiency virus and may increase the risk of neuroAIDS. As neuroAIDS is associated with altered microglial reactivity, the combined effects of human immunodeficiency virus‐Tat and morphine were determined in cultured microglia. Specifically, experiments determined the effects of Tat and morphine on microglial‐free radical production and oxidative stress, and on cytokine release. Data show that combined Tat and morphine cause early and synergistic increases in reactive oxygen species, with concomitant increases in protein oxidation. Furthermore, combined Tat and morphine, but not Tat or morphine alone, cause reversible decreases in proteasome activity. The effects of morphine on free radical production and oxidative stress are prevented by pre‐treatment with naloxone, illustrating the important role of opioid receptor activation in these phenomena. While Tat is well known to induce cytokine release from cultured microglia, morphine decreases Tat‐induced release of the cytokines tumor necrosis factor‐α and interleukin‐6, as well as the chemokine monocyte chemoattractant protein‐1 (MCP‐1). Finally, experiments using the reversible proteasome inhibitor MG115 show that temporary, non‐cytotoxic decreases in proteasome activity increase protein oxidation and decrease tumor necrosis factor‐α, interleukin‐6, and MCP‐1 release from microglia. Taken together, these data suggest that oxidative stress and proteasome inhibition may be involved in the immunomodulatory properties of opioid receptor activation in microglia.