sm-346 has been researched along with Brain-Ischemia* in 6 studies
6 other study(ies) available for sm-346 and Brain-Ischemia
Article | Year |
---|---|
Activation of σ1 and σ2 receptors by afobazole increases glial cell survival and prevents glial cell activation and nitrosative stress after ischemic stroke.
Activation of sigma receptors at delayed time points has been shown to decrease injury following ischemic stroke. The mixed σ1/σ2 receptor agonist, 5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole (afobazole), provides superior long-term outcomes compared to other σ ligands in the rat middle cerebral artery occlusion (MCAO) stroke model. Experiments using the MCAO model were carried out to determine the molecular mechanism involved in the beneficial effects of afobazole. Administration of afobazole (3 mg/kg) at delayed time points post-stroke significantly increased the number of microglia and astrocytes detected in the ipsilateral hemisphere at 96 h post-surgery. Morphological analysis of the microglia indicated that a greater number of these cells were found in the ramified resting state in MCAO animals treated with afobazole relative to MCAO vehicle controls. Similarly, fewer reactive astrocytes were detected in the injured hemisphere of afobazole-treated animals. Both the enhanced survival and reduced activation of glial cells were abolished by co-application of either a σ1 (BD-1063) or a σ2 (SM-21) receptor antagonist with afobazole. To gain further insight into the mechanisms by which afobazole lessens stroke injury, we probed the brain sections for markers of neuroinflammation (tumor necrosis factor α) and nitrosative stress (S-nitrosocysteine). Data show that afobazole significantly reduces S-nitrosocysteine levels, but does not alter tumor necrosis factor α expression 96 h after an ischemic stroke. Taken together our data indicate that afobazole acting via both σ1 and σ2 receptors decreases stroke injury by enhancing glial cell survival, blocking ischemia-induced glial cell activation, and decreasing nitrosative stress. Topics: Animals; Astrocytes; Benzimidazoles; Brain; Brain Ischemia; Butyrates; Cell Survival; Cysteine; Infarction, Middle Cerebral Artery; Macrophage Activation; Morpholines; Neuroglia; Neuroprotective Agents; Piperazines; Rats; Receptors, sigma; S-Nitrosothiols; Sigma-1 Receptor; Stroke; Tropanes | 2016 |
Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes.
There is currently a significant lack of therapeutic options for acute ischemic stroke, and no drug has been approved for treating patients at delayed time points (≥6h post-stroke). Afobazole, an anxiolytic currently used clinically in Russia, has been shown to reduce neuronal and glial cell injury in vitro following ischemia. Experiments using the permanent middle cerebral artery occlusion (MCAO) rat model were carried out to determine if afobazole can reduce ischemic stroke damage in vivo and expand the therapeutic window for stroke treatment. Post-stroke (24h) application of afobazole (0.3-3mg/kg) significantly decreased infarct volume at 96h post-surgery, as determined by Fluoro-Jade and NeuN staining of brain sections. Moreover, afobazole helped preserve both the levels and normal histological distribution of myelin basic protein, indicating a reduction in white matter injury. A time-dependence study showed that either pre-treatment or treatment started 6 to 48h post-stroke with the drug yields improved outcomes at 96h. The decrease in infarct volume produced by afobazole was blocked by the application of either a σ-1 (BD 1063, 30mg/kg) or a σ-2 (SM-21, 1mg/kg) antagonist, indicating that both receptor subtypes are involved in the effects of afobazole. Treatment with afobazole starting at 24h post-stroke resulted in enhanced survival one month following surgery. Behavioral testing of animals 28-32days post-surgery using the elevated body swing and forelimb grip-strength tests revealed that treatment with afobazole starting 24h post-stroke significantly reduces behavioral deficits caused by ischemic stroke. The increase in survival and improved functional outcomes are accompanied by a reduction in infarct volume, as determined by thionin staining of brain sections. Taken together, our data support the use of afobazole as a post-stroke pharmacological agent to expand the current therapeutic window. Topics: Animals; Benzimidazoles; Brain Ischemia; Hand Strength; Infarction, Middle Cerebral Artery; Male; Morpholines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Stroke; Treatment Outcome | 2014 |
Afobazole modulates microglial function via activation of both sigma-1 and sigma-2 receptors.
Microglial cells play a critical role in the neuroinflammatory response that accompanies various diseases of the central nervous system, such as ischemic stroke, and ATP is a major signaling molecule regulating the response of these cells to these pathophysiological conditions. Experiments were carried out to determine the effects of afobazole on microglial function and to identify the molecular mechanisms by which afobazole affects microglial cells. Afobazole was found to inhibit migration of microglial cells in response to ATP and UTP chemoattraction in a concentration-dependent manner. Inhibition of either σ-1 or σ-2 receptors decreased the effects of afobazole on microglia. In addition to inhibiting microglial cell migration, activation of σ receptors by afobazole decreased intracellular calcium elevation produced by focal application of ATP and UTP in isolated microglial cells. Furthermore, afobazole blocked membrane currents elicited by rapid application of ATP in microglial cells. Taken together, our data indicate that afobazole inhibits microglial response to P2Y and P2X purinergic receptor activation by functioning as a pan-selective σ-receptor agonist. In addition to modulating response to purinergic receptor activation, the effects of afobazole on microglial survival during in vitro ischemia were assessed. Application of afobazole during in vitro ischemia decreased microglial cell death during the ischemic episode and after a 24-h recovery period. Moreover, when afobazole was only applied after the ischemic episode, a significant enhancement in cell survival was still observed. Thus, afobazole acts via σ receptors to decrease microglial response to ATP and provides cytoprotection during and after ischemia. Topics: Adenosine Triphosphate; Animals; Anti-Anxiety Agents; Benzimidazoles; Brain Ischemia; Butyrates; Calcium; Cell Death; Cell Survival; Ethylenediamines; Female; Membrane Potentials; Microglia; Morpholines; Patch-Clamp Techniques; Piperazines; Pregnancy; Purinergic P2X Receptor Antagonists; Purinergic P2Y Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor; Tropanes; Uridine Triphosphate | 2011 |
Afobazole modulates neuronal response to ischemia and acidosis via activation of sigma-1 receptors.
Afobazole is an anxiolytic medication that has been previously shown to be neuroprotective both in vitro and in vivo. However, the mechanism(s) by which afobazole can enhance neuronal survival remain poorly understood. Experiments were carried out to determine whether afobazole can decrease intracellular calcium overload associated with ischemia and acidosis and whether the effects of afobazole are mediated via interaction of the compound with σ receptors. Fluorometric Ca(2+) imaging was used to resolve how application of afobazole affects intracellular Ca(2+) handling in cortical neurons. Application of afobazole significantly depressed, in a concentration-dependent and reversible manner, the intracellular Ca(2+) overload resulting from in vitro ischemia and acidosis. The IC(50) for afobazole inhibition of ischemia-evoked intracellular Ca(2+) overload was considerably less than that for the inhibition of [Ca(2+)](i) increases induced by acidosis. However, afobazole maximally inhibited only 70% of the ischemia-evoked intracellular Ca(2+) overload but effectively abolished intracellular Ca(2+) increases produced by acidosis. The effects of afobazole on ischemia- and acidosis-induced intracellular Ca(2+) dysregulation were inhibited by preincubating the neurons in the irreversible, pan-selective σ-receptor antagonist, metaphit. Moreover, the effects of afobazole on intracellular Ca(2+) increases triggered by acidosis and ischemia were blocked by the selective σ-1-receptor antagonists, BD 1063 and BD 1047, respectively. Experiments examining the effects of afobazole on neuronal survival in response to ischemia showed that afobazole was neuroprotective. Taken together, these data suggest that afobazole regulates intracellular Ca(2+) overload during ischemia and acidosis via activation of σ-1 receptors. This mechanism is probably responsible for afobazole-mediated neuroprotection. Topics: Acidosis; Animals; Anti-Anxiety Agents; Benzimidazoles; Brain Ischemia; Calcium; Cell Survival; Cerebral Cortex; Ethylenediamines; Female; Guanidines; Indicators and Reagents; L-Lactate Dehydrogenase; Membrane Potentials; Morpholines; Narcotics; Neurons; Patch-Clamp Techniques; Pentazocine; Phencyclidine; Piperazines; Pregnancy; Rats; Receptors, sigma; Sigma-1 Receptor | 2011 |
[Efficacy of aphobazole in the treatment of anxiety disorders in patients with chronic cerebro-vascular insufficiency].
Topics: Aged; Anti-Anxiety Agents; Anxiety Disorders; Benzimidazoles; Brain Ischemia; Female; Humans; Male; Middle Aged; Morpholines; Treatment Outcome | 2008 |
Neuroprotective effect of afobazole on rats with bilateral local photothrombosis of vessels in the prefrontal cortex.
We studied the neuroprotective effect of a new selective anxiolytic afobazole on rats with bilateral focal ischemic stroke in the prefrontal cortex caused by photothrombosis. Intraperitoneal injection of 5 mg/kg afobazole 1 h after surgery and over the next 8 days (daily treatment) produced a neuroprotective effect. Afobazole was far superior to the reference cerebroprotective drug cavinton (4 mg/kg) by neuroprotective activity. Topics: Animals; Anti-Anxiety Agents; Benzimidazoles; Blood Vessels; Brain Ischemia; Injections, Intraperitoneal; Light; Male; Mice; Morpholines; Motor Activity; Neuroprotective Agents; Prefrontal Cortex; Rats; Stroke | 2008 |