Evaluation of U-50,488H analogs for neuroprotective activity in the gerbil

Contreras, Patricia C.; Ragan, D M; Bremer, Margaret E.; Lanthorn, Thomas H.; Gray, Nancy M.; Iyengar, Smriti; Jacobson, Arthur E.; Rice, Kenner C.; Costa, Brian R. de

doi:10.1016/0006-8993(91)91161-s

Cited by 50 publications

(16 citation statements)

References 17 publications

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“…Ensuring that the volume of tissue being analyzed does not vary between groups can minimize the impact of these variables. This is easily accomplished using Cavalieri’s method which integrates area measurements from systematically random sampled reference sections throughout a 3-dimensional structure (Contreras, Ragan et al, 1991; Mayhew and Olsen, 1991; Costa, Mandarim-de-Lacerda et al, 1991). Should tissue volume vary between experimental groups, then microglia/macrophage cell counts or area measurements can be normalized to their respective reference volumes.…”

Section: Discussionmentioning

confidence: 99%

An efficient and reproducible method for quantifying macrophages in different experimental models of central nervous system pathology

Donnelly

Gensel

Ankeny

et al. 2009

Journal of Neuroscience Methods

121

101

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Historically, microglia/macrophages are quantified in the pathological central nervous system (CNS) by counting cell profiles then expressing the data as cells/mm 2 . However, because it is difficult to visualize individual cells in dense clusters and in most cases it is unimportant to know the absolute number of macrophages within lesioned tissue, alternative methods may be more efficient for quantifying the magnitude of the macrophage response in the context of different experimental variables (e.g., therapeutic intervention or time post-injury/infection). The present study provides the first in-depth comparison of different techniques commonly used to quantify microglial/ macrophage reactions in the pathological spinal cord. Individuals from the same and different laboratories applied techniques of digital image analysis (DIA), standard cell profile counting and a computer-assisted cell counting method with unbiased sampling to quantify macrophages in focal inflammatory lesions, disseminated lesions caused by autoimmune inflammation or at sites of spinal trauma. Our goal was to find a simple, rapid and sensitive method with minimal variability between trials and users. DIA was consistently the least variable and most time-efficient method for assessing the magnitude of macrophage responses across lesions and between users. When used to evaluate the efficacy of an anti-inflammatory treatment, DIA was 5-35x faster than cell counting and was sensitive enough to detect group differences while eliminating inter-user variability. Since lesions are clearly defined and single profiles of microglia/macrophages are difficult to discern in most pathological specimens of brain or spinal cord, DIA offers significant advantages over other techniques for quantifying activated macrophages.

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Section: Discussionmentioning

confidence: 99%

An efficient and reproducible method for quantifying macrophages in different experimental models of central nervous system pathology

Donnelly

Gensel

Ankeny

et al. 2009

Journal of Neuroscience Methods

121

101

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“…However, this may not necessarily be the case. These reports describe neuroprotection by sigma ligands in various in vivo models of neurodegeneration (Long et al, 1990;Contreras et al, 1991;Pontecorvo et al, 1991). In those studies, sigma compounds were administered in vivo and are likely to be present at the site of action in much lower concentrations than those used here.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability

1995

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The morphological effects of several neuroleptics as well as other novel and prototypic sigma ligands were examined by addition to cultures of C6 glioma cells. Sigma ligands caused loss of processes, assumption of spherical shape, and cessation of cell division. The time course and magnitude of this effect were dependent on the concentration of sigma ligand. Continued exposure to sigma compounds ultimately resulted in cell death. However, the morphological effect was reversible when sigma ligand was removed shortly after rounding. The potency of compounds to produce these effects generally correlated with binding affinity at sigma receptors of C6 glioma cell membranes labeled with [3H](+)-pentazocine. At a concentration of 100 microM, haloperidol, reduced haloperidol, fluphenazine, perphenazine, trifluoperazine, BD737, LR172, BD1008, and SH344 produced significant effects in 3–6 hr of exposure. Other compounds, such as trifluperidol, thioridazine, and (-)-butaclamol, produced significant effects by 24 hr of exposure. Despite the requirement of micromolar concentrations of ligand (some compounds were effective at 30 microM), the effect showed a remarkable specificity for compounds exhibiting sigma receptor binding affinity. Neuroleptics lacking potent sigma affinity [e.g., (-)- sulpiride, (+)-butaclamol, and clozapine] and other compounds that lack significant sigma affinity but that are agonists or antagonists at dopamine, serotonin, adrenergic, glutamate, phencyclidine, GABA, opiate, or muscarinic cholinergic receptors were without effect on cellular morphology at concentrations up to 300 microM over a period of 72 hr. Likewise, blockers and activators of Na+, K+, and Ca2+ channels and a monoamine oxidase inhibitor devoid of sigma affinity were without effect. Interestingly, 1,3-di-o-tolylguanidine (DTG), (+)-3-(3- hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP], (+)-pentazocine, (+)- cyclazocine, and other sigma-active benzomorphans and morphinans appeared inactive in up to 72 hr of culture. However, these compounds interacted synergistically with a subeffective dose of BD737 (30 microM) to produce effects usually in 6 hr or less. Also, the pH of the culture medium had a profound effect on the activity of sigma compounds. Increasing the pH from the normal range of 7.2–7.4 to pH 8.3– 8.5 shifted the dose curves (30, 100, 300 microM) for all sigma compounds to the left. Under these conditions, DTG, (+)-3-PPP, and benzomorphans produced effects in 24 hr or less.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Receptors are also implicated in the neurodegenerative processes involved in some diseases and some selective 1 -receptor ligands have demonstrated neuroprotective activity. 219,220,230,[232][233][234][235] Very recently, in our own laboratories, the aminoalkylpyridine (AAP) compounds (55, Fig. 20), have been found to act as potent, orally active anticonvulsant agents in the MES model, with long duration of action and no apparent signs of motor toxicity.…”

Section: 231mentioning

confidence: 99%

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

Lin¹,

Kadaba²

1997

Med. Res. Rev.

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Evaluation of U-50,488H analogs for neuroprotective activity in the gerbil

Cited by 50 publications

References 17 publications

An efficient and reproducible method for quantifying macrophages in different experimental models of central nervous system pathology

An efficient and reproducible method for quantifying macrophages in different experimental models of central nervous system pathology

Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

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