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ISEL detection of apoptotic cells following TNF-a infusions and oral CPI-1189 treatment. Photomicrographs showing the neocortex adjacent to the cannula tract for representative Saline/Vehicle (A), TNF-a/Vehicle (B), and TNF-a/CPI-1189 (C) treated animals. Note the presence of apoptotic cells in the TNFa/vehicle treated animal (arrows in B) and the lack of apoptotic cells in the same brain region of the other two treatment groups (A and C). Insert in (B) shows a single apoptotic cell at 10006 magni®cation. Bar in (A) is 25 mm in length and indicates the magni®cation of all three photomicrographs. Abbreviations: c, cannula tract.
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AIDS dementia complex (ADC) is characterized by increased apoptosis, gliosis, and oxidative stress in the CNS, as well as a compromised blood-brain barrier. TNF-alpha has been shown to be elevated in AIDS dementia complex brains and may contribute to AIDS dementia complex. To model elevated TNF-alpha in AIDS dementia complex, TNF-alpha was infused...
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... at P40.05. the TNF/Veh treated group (P40.05) and was not signi®cantly different from the Sal/Veh group. Figure 2 shows apoptotic cells in the neocortical tissue near the cannula tract stained for apoptosis. The neocortical tissue of the Sal/Veh treated animal ( Figure 2A) and TNF/CPI treated animal ( Figure 2C) is clear of apoptosis in the neocortical parenchyma, while the animal treated with TNF-a alone, shows several apoptotic cells ( Figure 2B). ...
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... 2 shows apoptotic cells in the neocortical tissue near the cannula tract stained for apoptosis. The neocortical tissue of the Sal/Veh treated animal ( Figure 2A) and TNF/CPI treated animal ( Figure 2C) is clear of apoptosis in the neocortical parenchyma, while the animal treated with TNF-a alone, shows several apoptotic cells ( Figure 2B). An enlargement of an apoptotic cell can be seen in the inset of Figure 2B. ...
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... 2 shows apoptotic cells in the neocortical tissue near the cannula tract stained for apoptosis. The neocortical tissue of the Sal/Veh treated animal ( Figure 2A) and TNF/CPI treated animal ( Figure 2C) is clear of apoptosis in the neocortical parenchyma, while the animal treated with TNF-a alone, shows several apoptotic cells ( Figure 2B). An enlargement of an apoptotic cell can be seen in the inset of Figure 2B. ...
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... 2 shows apoptotic cells in the neocortical tissue near the cannula tract stained for apoptosis. The neocortical tissue of the Sal/Veh treated animal ( Figure 2A) and TNF/CPI treated animal ( Figure 2C) is clear of apoptosis in the neocortical parenchyma, while the animal treated with TNF-a alone, shows several apoptotic cells ( Figure 2B). An enlargement of an apoptotic cell can be seen in the inset of Figure 2B. ...
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... neocortical tissue of the Sal/Veh treated animal ( Figure 2A) and TNF/CPI treated animal ( Figure 2C) is clear of apoptosis in the neocortical parenchyma, while the animal treated with TNF-a alone, shows several apoptotic cells ( Figure 2B). An enlargement of an apoptotic cell can be seen in the inset of Figure 2B. ...
Citations
... Both of these cytokines are elevated following TNBS administration [11][12][13][14] and treatment with an IL-1 receptor antagonist [15,16] and antibodies against TNF-α [13] reportedly ameliorate the effect of TNBS in rodents. Consistent with this possibility, CPI-1189 was recently shown to prevent TNF-α induced apoptosis in vitro [17,18] to protect against TNF-α induced weight loss, cognitive deficits and cell death in vivo [19,20] and to prevent the induction of stress activated protein kinases (p38MAPK) by IL-1β in vitro [21] . Alternatively the protective effects of CPI-1189 against colonic damage in this rat model may arise from its ability to alter the cascade of oxidative events associated with TNBS treatment [22,23] . ...
Nitrone-related therapeutics (NRTs) represents a new class of molecules that may be effective in treating inflammatory conditions. The goal of this study was to examine the effect of CPI- 1189 in a rat model of inflammatory bowel disease (IBD). Colonic inflammation was induced by an enema of trinitrobenzene sulfonic acid (TNBS). Saline-enema treated rats served as controls. After 3 days colonic damage was assessed morphologically using a validated scoring system and through measurement of myeloperoxidase (MPO), an enzymatic marker of inflammation. We found that a dose- dependent protection from TNBS-induced colonic damage was observed in rats given 10-70 mg kg¯ 1 of CPI-1189 treated p.o. 1 hr. before the TNBS enema. Consistent with the 55% absolute oral bioavailability of CPI-1189, greater protection (77%) was seen when CPI-1189 (30 mg kg¯1) was administered intravenously 1 hr. before the TNBS enema. In a separate series of healing experiments where CPI-1189 was administer after the TNBS inflammatory response had peaked, CPI-1189 at a dose of 90 mg kg¯1 p.o. reduced the TNBS colitis. CPI-1189 prevents and heals TNBS-induced colonic damage in rats suggesting that CPI-1189 may be a novel agent for the treatment of IBD.
... SB203580 (GlaxoSmithKline) is a broadband p38 inhibitor that is being replaced by more-specifically targeted compounds. In HIV-dementia clinical trials, an inhibitor of p38 phosphorylation (CPI-1189, developed by Centaur) was thought to provide protection by inhibiting neuronal apoptosis [56,57]. Another compound (SD31169, developed by Scios) inhibits the activity of phosphorylated p38 MAPK. ...
Neuroinflammation is a proinflammatory cytokine-mediated process that can be provoked by systemic tissue injury but it is most often associated with direct injury to the nervous system. It involves neural-immune interactions that activate immune cells, glial cells and neurons and can lead to the debilitating pain state known as neuropathic pain. It occurs most commonly with injury to peripheral nerves and involves axonal injury with Wallerian degeneration mediated by hematogenous macrophages. Therapy is problematic but new trials with anti-cytokine agents, cytokine receptor antibodies, cytokine-signaling inhibitors, and glial and neuron stabilizers provide hope for future success in treating neuropathic pain.
... One initially promising compound, CPI-1189, demonstrated no improvement in cognitive or functional assessments in one short clinical trial. [61][62][63][64] However, the ability of CPI-1189 to inhibit JNK and p38 and/or activate ERK is inconsistent in the literature. 63,65 Several potent inhibitors of JNK and p38 pathways are currently available (and in some cases in clinical trials). ...
Central nervous system (CNS) disease is a frequent complication of human immunodeficiency virus (HIV)-1 infection. Identification of cellular mechanisms that control virus replication and that mediate development of HIV-associated neuropathology will provide novel strategies for therapeutic intervention. The milieu of the CNS during HIV infection is extraordinarily complex because of infiltration of inflammatory cells and production of chemokines, cytokines, and neurotoxic molecules. Cells in the CNS must integrate signaling pathways activated simultaneously by products of virus replication and infiltrating immune cells. In this study, we examined activation of mitogen-activated protein kinases (MAPKs) in the CNS of simian immunodeficiency virus-infected macaques during acute, asymptomatic, and terminal infection. We demonstrate that significantly increased (P < 0.02) activation of ERK MAPK, typically associated with anti-apoptotic and neuroprotective pathways, occurs predominantly in astrocytes and immediately precedes suppression of virus replication and macrophage activation that occur after acute infection. In contrast, significantly increased activation of proapoptotic, neurodegenerative MAPKs JNK (P = 0.03; predominantly in macrophages/microglia), and p38 (P = 0.03; predominantly in neurons and astrocytes) after acute infection correlates with subsequent resurgent virus replication and development of neurological lesions. This shift from classically neuroprotective to neurodegenerative MAPK pathways suggests that agents that inhibit activation of JNK/p38 may be protective against HIV-associated CNS disease.
... Methods. The study was a randomized, double-blind, controlled trial comparing two doses of CPI-1189 with placebo over a 10-week first phase, followed by an optional 12 weeks of open-label experience with CPI-1189 (see figure E-1 on the Neurology Web site; go to www.neurology.org and scroll down the Table of Contents to find the title link for this article). ...
... It protected behavioral learning in rats when TNF␣ was administered intraventricularly. 12 HIV-induced apoptosis was inhibited in in vitro human brain aggregates, and more recent studies suggest CPI-1189 may have direct or indirect mechanisms bolstering neuronal survival factors such as extracellular signal-related kinase (ERK) and c-JUN N-terminal kinase (JNK) 13 in the face of HIV in the nervous system. Substantial preclinical evidence supports investigation of this drug in humans, including evidence of neuroprotection with very low levels of CPI-1189 and an excellent pharmacologic profile, with good oral absorption, ability to cross the blood-brain barrier, and minimal toxicity in animal models. ...
... 11 These are repetitive and highly stereotyped limb movements that involve the legs and are characterized by extension of the great toe in combination with flexion of the ankle, knee, and sometimes hip. 7,12 Although PLMS can be present in other disorders (e.g., sleep apnea and narcolepsy), they are considered to be related to the severity of RLS. 8 RLS is usually treated with dopaminergic drugs, such as L-dopa, [13][14][15][16] bromocriptine, 17 pergolide, 18 and pramipexole. 19 However, the side-effects profile (e.g., nausea) and the likelihood of long-term complications associated with dopaminergic drugs 20 have driven the search for alternative nondopaminergic treatment options for at least some patients. ...
CPI-1189 is a compound with antioxidant properties that blocks tumor necrosis factor-alpha (TNFalpha) effects in animal models. It has neuroprotective properties in model systems for HIV-associated neurotoxicity and thus is a candidate for neuroprotective therapy in humans with HIV-associated CNS disease.
To assess the tolerability and safety of CPI-1189 in treating HIV-associated cognitive-motor impairment.
Sixty-four subjects with mild to moderate HIV-associated cognitive-motor impairment were randomized to receive either placebo or 50 or 100 mg daily of CPI-1189 in addition to optimal HIV therapy. Subjects were followed prospectively in a double-masked study for 10 weeks. The primary assessment was tolerability and safety of the compound. Secondary objectives examined neuropsychological and functional change associated with this treatment.
The study compound was well tolerated, with 91% of CPI-1189-treated subjects and 76% of placebo-treated subjects completing the trial. Skin rash was seen equally in placebo and active arms, but the only study withdrawals due to skin rash occurred in CPI-1189-treated subjects (n = 2). One subject developed a cataract on drug (100 mg/day). CD4 lymphocyte counts and plasma HIV viral load remained stable in all groups throughout the trial. No significant treatment effects were observed on the change in composite Z-scores for eight neuropsychologic measures (NPZ-8). The Grooved Pegboard Test (nondominant) showed improved performance with CPI-1189 at 100 mg/day (p = 0.01), but no other neuropsychometric or functional measures demonstrated significant improvement.
CPI-1189 was well tolerated in HIV subjects with cognitive-motor disorder. This study was not powered to conclusively determine efficacy and showed no consistent treatment-associated improvement in cognitive or functional measures.
Purpose: The aim of the study was to determine the dental status, level, and structure of dental diseases, as well as to identify some clinical and functional deviations in the organs and tissues of the oral cavity among workers in certain industrial enterprises. Methodology: A comprehensive dental examination was conducted on 1600 individuals, including 420 from the Fergana Oil Refinery Plant (FNPP - main group (MG)-1), 425 from the Almalyk Mining and Metallurgical Plant (AGMK - MG-2), and 605 from the Navoi Chemical Plant (NavCP - MG-3), as well as 150 patients as a control group (CG) who visited a dental clinic. Tooth sensitivity (TS), pain and discriminatory sensitivity (PS and DS) of the oral mucosa, taste perception threshold, and functional mobility of the taste receptors on the tongue, enamel resistance to caries, microhardness (MH) of enamel and dentin, and the condition of periodontal tissues and pH of mixed saliva were determined. The data obtained were processed using statistical methods. Findings: It was determined that the levels and relative weights of the main dental diseases among workers in the studied industries remain quite high; carious and non-carious lesions of the tooth hard tissues, deformation and defects of teeth and dental rows (18.5%), periodontal tissue diseases (74.7%), diseases of the oral mucosa - 38.7%; the need for prosthetics (58.4%) and other pathologies. Additionally, almost all clinical and functional indicators and local non-specific reactivity of the tissues of the oral cavity in workers were disrupted. Unique Contribution to Theory, Policy and Practice: The presence of the main dental diseases among those surveyed from the studied groups is quite high, with noted reductions in the excitability threshold of teeth, around tooth tissues and the oral mucosa, disruption of PS and DS of the oral mucosa, as well as deterioration of the condition of tooth hard tissues. Based on the obtained results, the authors suggest continuing in-depth scientific research with the aim of developing effective methods for the diagnosis and prevention of dental diseases among workers in these industries.
Oxygen glucose deprivation (OGD)/re-oxygenation (OGDR) induces profound oxidative injury and neuronal cell death. It mimics ischemia-reperfusion neuronal injury. CPI-1189 is a novel tumor necrosis factor alpha-inhibiting compound with potential neuroprotective function. Here in SH-SY5Y neuronal cells and primary murine cortical neurons, CPI-1189 pretreatment potently inhibited OGDR-induced viability reduction and cell death. In OGDR-stimulated neuronal cells, p38 phosphorylation was blocked by CPI-1189. In addition, CPI-1189 alleviated OGDR-induced reactive oxygen species production, lipid peroxidation, and glutathione consumption. OGDR-induced neuronal cell apoptosis was also inhibited by CPI-1189 pretreatment. Furthermore, in SH-SY5Y cells and cortical neurons, CPI-1189 alleviated OGDR-induced programmed necrosis by inhibiting mitochondrial p53-cyclophilin D-adenine nucleotide translocase 1 association, mitochondrial depolarization, and lactate dehydrogenase release to the medium. In summary, CPI-1189 potently inhibited OGDR-induced oxidative injury and neuronal cell death.
Cognition enhancers are drugs able to facilitate attentional abilities and acquisition, storage and retrieval of information, and to attenuate the impairment of cognitive functions associated with head traumas, stroke, age and agerelated pathologies such as MCI and AD. Development of cognition enhancers is still a difficult task because of the complexity of the brain functions, poor predictivity of animal tests and lengthy and expensive clinical trials. Current research is based on several working hypotheses, derived from the progress of knowledge in the neuro-bio-pathology of cognitive processes. Approaches followed to develop cognition enhancing drugs, the results obtained in the past few years (since 2000) and the most promising molecules under study are reviewed.
A large number of chemical enteties, immunogens and topical medications, either synthetic or naturally occuring, against HIV have been brought into focus to combat AIDS epidemic. The three major classes of anti-HIV medications, leading to the development of synthetic drugs worldwide, belong to NRTs, NNRTIs and protease inhibitors. These have been discussed in detail with regard to HIV infected patients. A large number of natural products isolated from various plant species, flora and fauna have been described in detail. Some of these compounds have the potential for development as future drugs for cure of AIDS and could be helpful in replacement of combination therapy presently prevalent for treatment of HIV patients. Proteomics and Genomics are vital cores of biotechnology for prime consideration in lead generation aginst HIV. The recent aspects of development of combination therapy as well as the development of vaccines for treatment of AIDS, which are of current interest to clinicians, biologists and medicinal chemists also being discussed.
Individuals infected with the human immunodeficiency virus (HIV) often experience a dementia characterized by mental slowing and memory loss. Motor dysfunction may also accompany this condition. The pathogenesis of the dementia is not known, but microscopic examination of brain tissue from those afflicted shows evidence of chronic inflammation, reactive gliosis and cell death. Neurotoxic factors produced from activated macrophage or microglial cells such as tumor necrosis factor-alpha (TNFalpha), gp120 and quinolinic acid have been implicated as agents for the cell death which often appears to occur by an apoptotic mechanism. CPI-1189, a drug currently undergoing clinical evaluation as a treatment for the dementia associated with AIDS, is shown in this paper to mitigate apoptosis induced by TNFalpha, gp120, and necrosis induced by quinolinic acid. In addition, CPI-1189 mitigates the cell death produced by supernatants from cultured macrophages obtained from patients with AIDS dementia. The exact mechanism by which CPI-1189 prevents neurotoxicity is not known; however, protection from TNFalpha and supernatant-induced toxicity does not appear to involve NFkappaB translocation, and appears to be associated with an increase in activated ERK-MAP kinase. These findings may have implications for other neurological diseases where apoptotic cell death contributes to neurodegeneration.
This review provides a subjective analysis of the advances in our understanding of the immunopathogenesis of HIV-associated dementia that have occurred over the past 12 months. The review will focus on the following areas: (i) the role of chemokines and cytokines; (ii) the role of astrocytes, astrocyte cell death and non-productive infection of astrocytes; (iii) a model of the neuropathogenesis of HIV-associated dementia and its impact on treatment paradigms and future research. The requirements for the development of HIV-associated dementia are immunosuppression, the loss of macrophage regulation, central nervous system HIV infection of microglia and macrophages with a neurovirulent HIV strain, restricted HIV infection of astrocytes, and astrocyte cell death, all of which lead to an intracellular milieu that is neurotoxic. This cascade can be prevented and probably reversed by the use of highly active antiretroviral therapy, which controls viral replication both systemically and centrally. However, for those patients who have resistant virus and persistently high levels of replication, or who develop resistance or toxicity, other treatment strategies need to be developed. The control of excessive microglial and macrophage activation or a diminution of astrocyte and neuronal apoptosis could have benefits in terms of cognitive function. We therefore need to develop further our understanding of the immunopathogenesis of HIV-associated dementia so that we can control a number of other steps in the cascade rather than simply controlling the viral replication.
