Christopher Power

Metalloproteinases in biology and pathology of the nervous system

Matrix metalloproteinases (MMPs) have been implicated in several diseases of the nervous system. Here we review the evidence that supports this idea and discuss the possible mechanisms of MMP action. We then consider some of the beneficial functions of MMPs during neural development and speculate on their roles in repair after brain injury. We also introduce a family of proteins known as ADAMs (a disintegrin and metalloproteinase), as some of the properties previously ascribed to MMPs are possibly the result of ADAM activity.

The promise of minocycline in neurology

The capacity of minocycline to alleviate disease for several neurological disorders in animals is increasingly being recognised. Indeed, that one drug alone can attenuate the severity of disease in stroke, multiple sclerosis, spinal-cord injury, Parkinsons disease, Huntingtons disease, and amyotrophic lateral sclerosis is astounding. In this review, we describe the evidence for the efficacy of minocycline in several animal models of neurological disease, discuss the mechanisms by which minocycline affects a range of neurological diseases with diverse causes, and introduce the emerging investigation of minocycline in clinical neurology. The encouraging results of minocycline in experimental neurology bode well for its therapeutic use in human neurological diseases.

Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases

Intracerebral hemorrhage (ICH) is characterized by parenchymal hematoma formation with surrounding inflammation. Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of neurological diseases defined by inflammation and cell death. To investigate the expression profile and pathogenic aspects of MMPs in ICH, we examined MMP expression in vivo using a collagenase‐induced rat model of ICH. ICH increased brain MMP‐2, ‐3, ‐7, and ‐9 mRNA levels relative to sham‐injected (control) animals in the vicinity of the hematoma, but MMP‐12 (macrophage metalloelastase) was the most highly induced MMP (>80‐fold). Immunohistochemistry showed MMP‐12 to be localized in activated monocytoid cells surrounding the hematoma. In vitro studies showed that thrombin, released during ICH, induced MMP‐12 expression in monocytoid cells, which was reduced by minocycline application. Similarly, in vivo minocycline treatment significantly reduced MMP‐12 levels in brain. Neuropathological studies disclosed marked glial activation and apoptosis after ICH that was reduced by minocycline treatment. Neurobehavioral outcomes also were improved with minocycline treatment compared with untreated ICH controls. Thus, select MMPs exhibit increased expression after ICH, whereas minocycline is neuroprotective after ICH by suppressing monocytoid cell activation and downregulating MMP‐12 expression.Ann Neurol 2003;53:731–742

Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination

Human endogenous retroviruses (HERVs) constitute 8% of the human genome and have been implicated in both health and disease. Increased HERV gene activity occurs in immunologically activated glia, although the consequences of HERV expression in the nervous system remain uncertain. Here, we report that the HERV-W encoded glycoprotein syncytin is upregulated in glial cells within acute demyelinating lesions of multiple sclerosis patients. Syncytin expression in astrocytes induced the release of redox reactants, which were cytotoxic to oligodendrocytes. Syncytin-mediated neuroinflammation and death of oligodendrocytes, with the ensuing neurobehavioral deficits, were prevented by the antioxidant ferulic acid in a mouse model of multiple sclerosis. Thus, syncytins proinflammatory properties in the nervous system demonstrate a novel role for an endogenous retrovirus protein, which may be a target for therapeutic intervention.

HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration

The mechanisms of neurodegeneration that result in human immunodeficiency virus (HIV) type 1 dementia have not yet been identified. Here, we report that HIV-infected macrophages secrete the zymogen matrix metalloproteinase-2 (MMP-2), which is activated by exposure to MT1-MMP on neurons. Stromal cell–derived factor 1α (SDF-1), a chemokine overexpressed by astrocytes during HIV infection, was converted to a highly neurotoxic protein after precise proteolytic processing by active MMP-2, which removed the N-terminal tetrapeptide. Implantation of cleaved SDF-1(5–67) into the basal ganglia of mice resulted in neuronal death and inflammation with ensuing neurobehavioral deficits that were abrogated by neutralizing antibodies to SDF-1 and an MMP inhibitor drug. Hence, this study identifies a new in vivo neurotoxic pathway in which cleavage of a chemokine by an induced metalloproteinase results in neuronal apoptosis that leads to neurodegeneration.

Interleukin-1β promotes oligodendrocyte death through glutamate excitotoxicity

Glutamate excitotoxicity is implicated in the progressive loss of oligodendrocytes in multiple sclerosis, but how glutamate metabolism is dysregulated in the disease remains unclear. Because there is microglia activation in all stages of multiple sclerosis, we determined whether a microglia product, interleukin‐1β, could provide the mechanism for glutamate excitotoxicity. We found that whereas interleukin‐1β did not kill oligodendrocytes in pure culture, it produced apoptosis of oligodendrocytes in coculture with astrocytes and microglia. This requirement for a mixed glia environment suggests that interleukin‐1β impairs the well‐described glutamate‐buffering capacity of astrocytes. In support, antagonists at AMPA/kainate glutamate receptors, NBQX and CNQX, blocked the interleukin‐1β toxicity to oligodendrocytes. Another microglia/macrophage cytokine, tumor necrosis factor‐α, also evoked apoptosis of oligodendrocytes in a mixed glia environment in an NBQX‐blockable manner. These results provide a mechanistic link between the persistent and insidious microglia activation that is evident in all stages of multiple sclerosis, with the recent appreciation that glutamate excitotoxicity leads to the destruction of oligodendrocytes in the disease. Ann Neurol 2003;53:588–595

Monocyte activation and differentiation augment human endogenous retrovirus expression: Implications for inflammatory brain diseases

Human endogenous retroviruses (HERVs) have been implicated as causative agents in diseases characterized by inflammation and macrophage activation, such as multiple sclerosis. Because monocyte activation and differentiation influence retroviral transcription and replication, we investigated the contribution of these processes to the expression of four HERV families (HERV‐W, HERV‐K, HERV‐E, and HERV‐H) in human monocytes and autopsied brain tissue from patients with brain diseases associated with increased macrophage activity. Reverse transcriptase‐polymerase chain reaction analysis of primary macrophages and U937 monocytoid cells stimulated with phorbol‐12‐myristate‐13‐acetate or lipopolysaccharide revealed three‐ to ninefold increases in HERV‐W, HERV‐K, and HERV‐H RNA levels. In addition, elevated reverse transcriptase activity and HERV RNA were detectable in supernatants from PMA‐stimulated U937 cultures, properties that could be attenuated with the inhibitor of monocyte differentiation threonine‐lysine‐proline. In contrast, stimulation of monocytes decreased or had no effect on HERV‐E expression. Compared with controls, HERV‐W and HERV‐K expression was increased in brain tissue from patients with multiple sclerosis or human immunodeficiency virus infection or AIDS, with concomitant elevated tumor necrosis factor‐α levels. Similarly, elevated HERV‐W levels were detected in patients with Alzheimers dementia only when tumor necrosis factor‐α expression was also evident (2 of 6 cases). The detection of several HERVs in inflammatory brain diseases and the capacity to augment HERV expression in monocytes with compounds that influence cellular activity suggest that increased expression of these viruses is a consequence of increased immune activity rather than causative of distinct diseases.

Adenosine A2A receptor activation reduces proinflammatory events and decreases cell death following intracerebral hemorrhage

The ubiquitous neuromodulator adenosine inhibits the production of several proinflammatory cytokines through activation of specific cell‐surface adenosine receptors. We demonstrated recently that antisense oligonucleotides to tumor necrosis factor‐α (TNF‐α) are neuroprotective in a rat model of intracerebral hemorrhage. Therefore, we hypothesized that activation of adenosine receptors would provide protection against intracerebral hemorrhage‐induced TNF‐α production and inflammatory events. In vitro experiments showed that adenosine A1, A2A, and A3 receptor subtypes were present on U937 cells, and activation of these subtypes inhibited TNF‐α production with a rank order of A2A >> A1 > A3. Prolonged treatment of U937 cells with the A2A receptor agonist 2‐p‐(carboxyethyl)phenethylamino‐5′‐N‐ethylcarboxamidoadenosine hydrochloride (CGS 21680) desensitized adenosine A2A, A1, and A3 receptors. CGS 21680 administration directly into the striatum immediately prior to the induction of intracerebral hemorrhage inhibited TNF‐α mRNA and, 24 hours following induction, reduced parenchymal neutrophil infiltration (p < 0.001) and TUNEL‐positive cells (p < 0.002) within and bordering the hematoma. These results suggest that pharmacological strategies targeting A2A receptors may provide effective inhibition of acute neurotoxic proinflammatory events that occur following intracerebral hemorrhage.

HIV‐1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors

The release of potentially neurotoxic molecules by HIV‐infected brain macrophages is accompanied by neuronal injury and death that results in the development of HIV‐associated dementia (HAD). Among the potential neurotoxins implicated in the development of HAD is the HIV‐1 transactivating protein, Tat. To investigate the mechanism by which Tat causes neurotoxicity, brain‐derived Tat sequences from nondemented (Tat‐ND) and demented (Tat‐HAD) AIDS patients, which differed primarily in the augmenting region of Tat, were expressed in U937 monoblastoid cells and primary human macrophages. Cells expressing Tat‐HAD protein exhibited elevated matrix metalloproteinase (MMP)‐2 and ‐7 release and activation, but cells expressing Tat‐ND did not exhibit enhanced MMP expression. Conditioned media from Tat‐HAD–transfected cells caused significantly greater neuronal death (15.4 ± 4.3%) than did Tat‐ND (4.4 ± 2.1%) or nontransfected (2.1 ± 0.8%) cell‐derived conditioned media. The neurotoxicity induced by Tat‐HAD was inhibited by anti–MMP‐2 or ‐7 antibodies (p < 0.005) but not by antibodies against MMP‐9 or Tat. Similarly, scid/nod mice receiving striatal implants of Tat‐HAD–transfected cells exhibited greater neurobehavioral abnormalities and neuronal loss (p < 0.005) than did animals receiving Tat‐ND or nontransfected cells, which were reduced by treatment with the MMP inhibitor prinomastat (p < 0.005). These findings indicate that Tat causes neuronal death through an indirect mechanism that is Tat sequence dependent and involves the induction of MMPs. Ann Neurol 2001;49:230–241

Proteinase-activated receptors in the nervous system.

Recent data point to important roles for proteinases and their cognate proteinase-activated receptors (PARs) in the ontogeny and pathophysiology of the nervous system. PARs are a family of G-protein-coupled receptors that can affect neural cell proliferation, morphology and physiology. PARs also have important roles in neuroinflammatory and degenerative diseases such as human immunodeficiency virus-associated dementia, Alzheimers disease and pain. These receptors might also influence the pathogenesis of stroke and multiple sclerosis, conditions in which the blood–brain barrier is disrupted. The diversity of effects of PARs on neural function and their widespread distribution in the nervous system make them attractive therapeutic targets for neurological disorders. Here, we review the roles of PARs in the central and peripheral nervous systems during health and disease, with a focus on neuroinflammatory and degenerative disorders.