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Anesth Analg 2006;103:430-434
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000226133.85114.91

NEUROSURGICAL ANESTHESIA

Sigma 1 Receptor Agonists Act as Neuroprotective Drugs Through Inhibition of Inducible Nitric Oxide Synthase

Kamila Vagnerova, MD, Patricia D. Hurn, PhD, Anish Bhardwaj, MD, and Jeffrey R. Kirsch, MD

From the Department of Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, Portland, Oregon.

Address correspondence and reprint requests to Jeffrey R. Kirsch, MD, Professor, Department of Anesthesiology and Peri-Operative Medicine, OHSU, 3181 SW Sam Jackson Park Road UHS-2, 97239, Portland, OR 97239. Address e-mail to kirschje{at}ohsu.edu.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Postischemic administration of the sigma-1 agonists reduces ischemic brain injury; however, the mechanism is unclear. We hypothesized that the sigma-1 agonist (+)isoform of pentazocine (P(+)) reduces damage in part by ameliorating cell death mediated via inducible nitric oxide synthase (iNOS) and that the (–)isoform (P(–)) lacks this effect. We compared treatment with P(+) with or without the iNOS inhibitor aminoguanidine (AG) and also the effects of P(+) in iNOS deficient (iNOSKO) mice. A possible mechanism of neuroprotection is inhibition of iNOS expression. Male C57/Bl6 mice were subjected to transient middle cerebral artery occlusion (90 min) and drugs were administered with reperfusion: 1) P(+) with AG (P+/AG), 2) P(+), 3) P(–), 4) AG, or 5) placebo. iNOSKOs were treated with either P(+) or placebo. Infarction (triphenyltetrazolium chloride histology, 72 h) was reduced by P(+) treatment in striatum by 44% and in neocortex by 23% versus placebo (P < 0.05), a reduction comparable to AG effect. P(–) did not attenuate brain injury. There was no difference in P(+)/AG treatment compared with showed the same level of neuroprotection as P(+) alone. P(+) also did not provide further neuroprotection for iNOSKOs. We conclude that postischemic administration of P(+) reduces infarct volume in mice. Because AG provides no additional benefit to P(+) treatment and iNOSKOs do not benefit from P(+), we speculate that P(+) acts by suppressing cell death resulting from iNOS toxicity.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Numerous studies have demonstrated the robust neuroprotective properties of sigma-1 receptor agonists in animal models of cerebral ischemia (1–4). We have demonstrated previously (4) that the potent sigma-1 receptor agonist 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) attenuates infarction volume in the cat, rat (1,3), and mouse (5) after transient middle cerebral artery occlusion (MCAO) and that the dextro- (+) isoform of sigma-1 receptor agonist pentazocine (+) stereospecifically reduces brain injury after MCAO in rats (2).

The sigma-1 receptor is a 223 amino-acid protein (6) distributed in neural and non-neural tissues and is characterized by unique ligand specificity (7). Sigma-1 receptor mRNA is concentrated in specific areas of the brain, including the olfactory bulb, hippocampus, hypothalamus, cortex, or cerebellum and expression is not affected during aging in mice (8). Sigma receptors may be important in regulation of motor, sensory, emotional, and memory function. Sigma-1 receptor agonists have antiamnesic, antistress, antidepressant (7), and antiaddictive properties (9).

Not surprisingly, sigma-1 receptor agonists interact with a number of excitatory neurotransmitter systems in brain (10). A variety of antiexcitotoxic mechanisms for sigma-1 agonists have been implicated that could account, in part, for the neuroprotective properties of this class of compounds. For example, sigma ligands inhibit ischemia-induced presynaptic glutamate release (11), attenuate postsynaptic glutamate-evoked Ca2+ influx (12), modulate neuronal responses to N-methyl-d-aspartate (NMDA) receptor stimulation (13,14), inhibit dopaminergic neurotransmission, attenuate glutamate- and NMDA-induced nitric oxide (NO) synthase (NOS) activation in vitro (15), and attenuate ischemia-evoked NO production in vivo (13).

Sigma-1 receptor agonists provide robust neuroprotection from focal cerebral ischemia injury when administered during reperfusion (5). This observation suggests that sigma-1 receptor activation may lead to suppression of reperfusion injury in addition to impacting intraischemic events. Others have demonstrated that NO produced by inducible NOS (iNOS) is an important contributor to delayed postischemic injury (16). We have shown previously that NO production during ischemia and early reperfusion is attenuated by the sigma-1 receptor agonist PPBP in the rat (13). We hypothesized that PPBP acts upstream from NO generation and subsequent in vivo data suggested that the effect is linked to reduced neuronal NOS (nNOS) activity (5). However, in the past study we did not evaluate the potential role of NO produced by an iNOS pathway. In the present study, we hypothesized that administration of the sigma-1 receptor agonist (+) pentazocine (P(+)) would minimize postischemic brain injury by a mechanism that involves reduced NO production via an iNOS pathway. We previously demonstrated that P(+) treatment is associated with stereospecific neuroprotective effects after focal ischemia in rats (2). To determine whether P(+) acts through a mechanism involving iNOS, we compared the effects of P(+) alone or in combination with the iNOS inhibitor aminoguanidine (AG) (16) and in iNOS–deficient (knockout) (iNOSKO) mice on outcome from transient MCAO.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study was conducted in accordance with National Institutes of Health guidelines for the use of experimental animals, and the institutional Animal Care and Use Committee approved the protocols. All methods were as previously described (5,17). Age-matched, sexually mature male mice (C57BL/6J) were used in all experiments. iNOSKO mice were compared with genetic wild-type (WT) controls (Jackson Laboratories). Cerebral ischemia was induced by reversible MCAO, as previously published (5,17). In brief, mice were anesthetized with 1.5% to 2.0% halothane in oxygen-enriched air by snout mask, and rectal temperatures were controlled at 36.5°C ± 0.6°C with heating pads. The common carotid artery was exposed and reversibly ligated, then the external carotid artery was ligated and cauterized. Unilateral MCAO was performed by inserting a 6-0 nylon monofilament surgical suture with heat-blunted tip into the internal carotid artery via the external carotid artery stump. The tip was positioned at a distance of 6 mm beyond the internal carotid/pterygopalatine artery bifurcation, and occlusion was confirmed by a laser Doppler flow (LDF; Moor Instruments) probe positioned over the ipsilateral hemisphere at the mid ear-to-eye distance. The suture was then secured in place, and the animal was awakened and singly housed. Neurological deficit was confirmed during continuous occlusion by a scoring system: 0 = no deficit, 1 = failure to extend forelimb, 2 = circling, 3 = unilateral weakness, 4 = no spontaneous motor activity (17,18). Mice with clear neurological deficits (neurological deficit scoring ≥2) were re-anesthetized for osmotic pump implantation and removal of the occluding filament at 90 min, end-occlusion. Animals randomized to (+) or (–) pentazocine (P) treatment (Sigma Aldrich, St. Louis, MO) at doses 2 mg · kg–1 · h–1 (2) or vehicle (phosphate-buffered saline) were implanted intraabdominally with an osmotic pump (2001D Alzet minipump, 200 µL volume) and IV catheter device that was placed into the right external jugular vein. Treatment was initiated 5 min before reperfusion and continued for 24 h. Additional cohorts were randomized to IP AG treatment (Sigma Aldrich, 200 mg/kg) (16) or normal saline (NS) vehicle administered twice a day for 3 days; initial treatment at 18 h of reperfusion. Animals were housed in individual cages and given access to food and water, ad libitum. Lastly, cohorts of male iNOSKO and WT mice (Jackson Laboratories) were randomized to IV (+) P or NS and IP NS vehicle injection twice a day.

Postischemic neurological assessment (17) was performed daily (24 h, 48 h, 72 h after MCAO). At 72 h, the animals were decapitated under deep anesthesia (5% halothane). The brains were harvested and sliced into five 2-mm thick coronal sections for staining with 1.2% triphenyltetrazolium chloride (Sigma) in saline (2,5,13). Infarction volume was measured using digital imaging (MTI Series 68 video camera) and image analysis software (Sigma Scan Pro, Jandel).

The area of infarct was measured on the rostral and caudal surfaces of each slice and numerically integrated across the thickness of the slice to obtain an estimate of infarct volume in each slice. Measurement was made of total infarct volume, striatal infarct volume, and cortical infarct volume. Volumes from all five slices were summed to calculate total infarct volume expressed as a percentage of contralateral structure volume. Infarct volume was corrected for edema by comparing the volume of ischemic to nonischemic hemispheres (5). All measurements were performed by an investigator blinded as to treatment assignment.

Physiological measurements were performed in separate cohorts (n = 3 per group), as previously described (5,17). In each animal, a femoral arterial catheter was placed for arterial blood pressure and blood gas measurement (pH, Pco2, Po2, HCO3, SBE, sat O2, hemoglobin). Baseline (before MCAO) and intraischemic (during MCAO) cortical LDF were also determined. LDF was recorded as a percentage of the baseline values.

All data are expressed as mean ± sem. Physiological and behavioral variables were analyzed by two-way analysis of variance, and Newman-Keuls test was used post hoc to detect differences among groups. Infarction volumes were analyzed by one-way analysis of variance, and post hoc comparisons were made by using Tukey test. The criterion for statistical significance was set at P < 0.05.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Pentazocine and Aminoguanidine Experiment
Intraischemic physiological variables and LDF showed no differences among treatment groups. Infarction volume at 72 h of reperfusion was reduced by P(+) treatment in the cerebral cortex (27.7% ± 5.6%) and caudate putamen (47.6% ± 8.6%) as compared with the vehicle control group (cortex: 51.2% ± 4.5%, P < 0.05 and caudate: 92.3% ± 7.4%, P < 0.001) (Fig. 1). Despite these differences, behavioral outcomes scores were not improved by P(+) treatment. As expected, P(–) did not attenuate brain injury as compared with the vehicle group. There was no difference for injury volume in mice treated with combined P(+) and AG as compared to P(+) alone (cerebral cortex P = 0.94, caudate putamen P = 0.99) (Fig. 1(A), 1(B)). Neurobehavioral deficit was not significantly different among treatment groups (Fig. 2).


Figure 129
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  		Figure 1. A, Cerebral cortex infarction size in pentazocine experiment. Infarction size in neocortex was significantly (*P < 0.05) reduced by treatment with (+) pentazocine (P(+)) or aminoguanidine (AG) or their combination as compared with vehicle (ctrl) or P(–) treatment groups. Values are mean + sem. B, Caudate putamen infarction size in pentazocine experiment. Infarction size in caudate putamen was significantly (**P < 0.001) reduced by treatment with (+) pentazocine (P(+)) or aminoguanidine (AG) or their combination as compared with vehicle (ctrl) or P(–) treatment groups. Values are mean + sem.

 

Figure 229
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  		Figure 2. Neurological deficit score in pentazocine (P) experiment. Neurological deficit did not show significant differences among treatment groups. Values are mean ± sem.

 

iNOS Knockout Experiment
Intraischemic physiological variables and LDF showed no differences among treatment groups. Infarction volume was reduced in iNOSKO mice in cortex (27.3% ± 5.0%) and caudate putamen (48.9% ± 7.2%) as compared with WT controls (49.6% ± 6.5% and 76.7% ± 12.9%, respectively) (Fig. 3). Treatment with P(+) in iNOSKO mice as compared with no treatment (iNOSKO controls) had no statistically significant effect on the size of the injury in cortex (P = 0.37) or caudate putamen (P = 0.68). Neurobehavioral deficit was not significantly different among treatment groups (Fig. 4).


Figure 329
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  		Figure 3. A, Cerebral cortex infarction size in inducible nitric oxide synthase (iNOS) knockout experiment. Infarction size in neocortex was significantly (**P < 0.001) reduced in iNOS knockout (KO) animals and by treatment with (+) pentazocine (P(+)) or their combination (*P < 0.05) as compared to wild-type (WT) vehicle (ctrl) treatment group. Values are mean + sem. B, Caudate putamen infarction size in inducible nitric oxide synthase (iNOS)knockout experiment. Infarction size in striatum (caudate putamen) was significantly (*P < 0.05) reduced by treatment with (+) pentazocine (P(+)) in iNOS knockout (KO) animals as compared to wild-type (WT) vehicle (ctrl) treatment group. Values are mean + sem.

 

Figure 429
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  		Figure 4. Neurological deficit score in inducible nitric oxide synthase (iNOS) knockout experiment. Neurological deficit did not show significant differences among treatment groups. Values are mean ± sem. WT = wild-type.

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study demonstrates three important novel findings. First, sigma-1 receptor agonist P(+) provides significant neuroprotection in both cortex and striatum after focal cerebral ischemia. These results confirm that P(+) is as effective in the mouse as we have previously published in the rat (2). The lack of efficacy for the levo (–) isoform P(–) suggests that stereospecificity is required in mice, as in the rat. Second, P(+) improves ischemic outcomes when administered during reperfusion (5), suggesting a suppression of reperfusion injury. Third, combined treatment with AG does not provide significant additional protection to P(+) treatment alone, nor does P(+) improve outcome in iNOSKO mice. We conclude that AG and P(+) may act by a similar mechanism involving inhibition of iNOS activity.

Sigma-1 receptor is widely expressed in the mammalian brain including human brain (6,7). In mouse brain, structures which contain the sigma-1 receptor and are relevant to our ischemic model are the neocortex and caudate putamen (8). Expression appears to be similar in both the mouse and rat (19). Subcellular immunostaining localization studies identify receptors in both neuronal cell bodies and dendrites (8,19), particularly within postsynaptic thickenings, although also observed at the presynaptic level. All subcellular localizations are consistent with the purported role of the receptor as modulator of Ca2+ mobilization. The mechanism of its activation has not been elucidated, nor has the endogenous ligand been identified (8).

We have previously observed that sigma-1 receptor agonists, P(+) and PPBP, provide histological neuroprotection in models of transient focal cerebral ischemia (2,3). Numerous protective mechanisms may be involved. Local administration of sigma-1 receptor agonist PPBP into striatum rapidly suppresses NMDA-induced nNOS activity, as measured by microdialysis (13). Furthermore, sigma-1 receptor ligands reduce NMDA-induced increases in intracellular Ca2+ (12), likely reducing Ca2+-dependent NOS activation. Accordingly, we and others have postulated that sigma-1 receptors modulate signals downstream of NMDA receptor and involving NOS activation (13,15). Interactions between PPBP and non-NMDA receptors with permissive Ca2+ entry have also been reported (20), leading to reduced mobilization of Ca2+ stores and reduced NO production. We have shown that PPBP suppresses ischemic NO production (5) and have begun to evaluate which NOS isoform is the target for PPBP's action. When PPBP is administered in conjunction with the selective nNOS inhibitor 7-NI, there is no additive histologic protection. Ischemic NO activity, as estimated by arginine to citrulline conversion in microdialysates is similar in PPBP- and 7-NI–treated animals (5). We now focus on Ca2+ independent iNOS, also expressed in neurons, endothelial cells, and microglia (21,22). iNOS is a deleterious mediator in ischemic pathology, and treatment with selective inhibitors (23) or genetic deletion (16,24) of iNOS improves infarct volume.

We compared the effect of P(+) to AG, at doses previously found to be neuroprotective (16) and at a survival end-point of 72 hours, a time frame in which iNOS likely contributes to cell death. AG has been well studied in the mouse and reduces iNO activity (16,21,24). We also used iNOS deficient mice and showed, as in previous reports (16,24), that these mice sustain reduced infarct volumes relative to WT controls. Our results support the hypothesis that P(+) acts via iNOS-linked mechanisms because P(+) did not significantly add to the efficacy of AG in WT mice. P(+) treatment also had no significant effect in iNOSKOs. However, our observations do not prove that other mechanisms, in addition to iNOS suppression, may be involved in the protective effect of the sigma-1 receptor agonists. For example, we have previously demonstrated an interaction between sigma-1 receptor agonists and nNOS (5). As with any transgenic species that has developed throughout life with a genetic mutation, we acknowledge the possibility of unique compensatory responses in iNOSKOs that may have obscured the benefit of P(+). We also did not measure iNOS activity directly in our experiments. However, the combined findings with pharmacological and genetic inhibition implicate iNOS as an important component of P(+)'s mechanism of protection in ischemic brain.

In contrast to improved histologic outcome, we did not observe improved behavioral outcomes among the P(+)-treated groups. This may have been attributable to a relative insensitivity of our scoring system in distinguishing gradual neurologic improvement. The 0–4 point scoring system can detect the major neurological deficits, but it proved to be insufficient for detecting fine neurological changes. Alternatively, the 72-hour survival time may have been appropriate as a time to assess infarct size but was suboptimal to demonstrate functional treatment effects. Using longer survival time and more detailed neurobehavioral assessment might help to uncover the potential neurological improvement.

In conclusion, this study demonstrates that sigma 1-receptor agonist P(+) affords significant neuroprotection in cortex and striatum after focal cerebral ischemia when administered during early reperfusion. Our data in aggregate suggest that sigma-1 receptor ligands suppress nNOS and iNOS activation during ischemia and reperfusion.

Therefore, we speculate that these drugs may be an effective pharmacological intervention in clinical ischemic brain injury.


   Footnotes
 
Accepted for publication April 10, 2006.

Supported, in part, by US Public Health Service, National Institutes of Health grant NS20020.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press