Prehospital EMS Triage for Acute Stroke Care.

Acute stroke has had major advances over the last two decades due to the introduction of pharmacologic and endovascular revascularization, which can improve functional outcome. Stroke systems of care have been developed to provide faster, more efficient care for stroke patients. A major part of these care pathways is prehospital care, when patients are triaged to appropriate levels of care. It is essential that prehospital scales are used accurately and effectively by emergency medical services to assist them with the triage process. New technologies including mobile stroke units, telemedicine, and wearable technology have been introduced as options for optimization of this emergent process.

Use of Wearable Technology in Remote Evaluation of Acute Stroke Patients: Feasibility and Reliability of a Google Glass-Based Device.

BACKGROUND: Telestroke is an efficient, cost-effective way to standardize care and improve access to immediate neurologic expertise for rural hospitals and other underserved areas. Hands-free wearable technology potentially allows for faster evaluations that fit easily within prehospital workflows and could improve prehospital triage of stroke patients to appropriate receiving stroke centers. The goal of this study is to assess the feasibility and inter-rater reliability of wearable eyeglass video technology in assessing stroke-related neurologic deficits in patients with suspected acute stroke. METHODS: Consecutive patients with suspected stroke were evaluated concurrently by an on-site neurologist using wearable eyeglass video technology and a remotely located neurologist viewing the patient through an online platform. Inter-rater reliability in assigning National Institutes of Health Stroke Scale (NIHSS) scores was evaluated using inter-rater correlation coefficient (ICC) and weighted kappa scores. RESULTS: Among 17 enrolled patients, mean age was 58 (SD ± 20) and 29% were female. There was a high degree of correlation in total NIHSS score (ICC .99 and weighted kappa .88) and across all NIHSS subitems (ICC .81-1 and weighted kappa .68-1) between the examiner evaluating remotely via wearable eyeglass video technology with access to the patient and the in-person examiner. The maximum difference between the 2 NIHSS scores was 3. CONCLUSIONS: The use of wearable eyeglass video technology in telestroke is feasible and reliable. Use of this technology in the prehospital setting has the potential to improve early assessment of patients with acute stroke symptoms and to facilitate transfer to appropriate stroke centers in the regional systems of care.

The Addition of Atrial Fibrillation to the Los Angeles Motor Scale May Improve Prediction of Large Vessel Occlusion.

BACKGROUND AND PURPOSE: There is evidence suggesting that Los Angeles Motor Scale (LAMS) ≥ 4 predicts large vessel occlusion (LVO). We aim to determine whether atrial fibrillation (AF) can improve the ability of LAMS in predicting LVO. METHODS: We included consecutive patients with a discharge diagnosis of ischemic stroke admitted within 24 hours from last known normal time who underwent emergent vascular imaging using a computerized tomography angiography (CTA) of the head and neck. LVO was defined as intracranial internal carotid artery, proximal middle cerebral artery (M1 or proximal M2 segment), or basilar occlusion. LAMS was determined in the emergency department upon arrival. Univariate and multivariable models were performed to identify predictors of LVO and to determine whether AF improves the ability of LAMS to predict LVO. RESULTS: Among 1,234 patients admitted with ischemic stroke, 862 underwent emergent vascular imaging (69.8%) out of which 374 (43.4%) had evidence of LVO and 207 (24%) underwent mechanical thrombectomy. In multivariable models, predictors of LVO were LAMS (OR 1.42 per one point increase 95% CI 1.29-1.57) and AF (OR 1.95 95% CI 1.26-3.02, P < .001). We developed the LAMS-AF that includes the LAMS score and adds two points if AF is present. In this analysis, LAMS-AF (AUC .78) had improved prediction over LAMS (AUC .76) in predicting LVO and lead to reclassification of 8/68 patients (11.8%) with LAMS = 3 group into the high-risk LVO group. CONCLUSION: In patients with LAMS = 3, using the LAMS-AF score may improve the ability of LAMS in predicting LVO. Larger studies are needed to confirm our findings.

Los Angeles Motor Scale to Identify Large Vessel Occlusion: Prehospital Validation and Comparison With Other Screens.

BACKGROUND AND PURPOSE: Prehospital scales have been developed to identify patients with acute cerebral ischemia (ACI) because of large vessel occlusion (LVO) for direct routing to Comprehensive Stroke Centers (CSCs), but few have been validated in the prehospital setting, and their impact on routing of patients with intracranial hemorrhage has not been delineated. The purpose of this study was to validate the Los Angeles Motor Scale (LAMS) for LVO and CSC-appropriate (LVO ACI and intracranial hemorrhage patients) recognition and compare the LAMS to other scales. METHODS: The performance of the LAMS, administered prehospital by paramedics to consecutive ambulance trial patients, was assessed in identifying (1) LVOs among all patients with ACI and (2) CSC-appropriate patients among all suspected strokes. Additionally, the LAMS administered postarrival was compared concurrently with 6 other scales proposed for paramedic use and the full National Institutes of Health Stroke Scale. RESULTS: Among 94 patients, age was 70 (±13) and 49% female. Final diagnoses were ACI in 76% (because of LVO in 48% and non-LVO in 28%), intracranial hemorrhage in 19%, and neurovascular mimic in 5%. The LAMS administered by paramedics in the field performed moderately well in identifying LVO among patients with ACI (C statistic, 0.79; accuracy, 0.72) and CSC-appropriate among all suspected stroke transports (C statistic, 0.80; accuracy, 0.72). When concurrently performed in the emergency department postarrival, the LAMS showed comparable or better accuracy versus the 7 comparator scales, for LVO among ACI (accuracies LAMS, 0.70; other scales, 0.62-0.68) and CSC-appropriate (accuracies LAMS, 0.73; other scales, 0.56-0.73). CONCLUSIONS: The LAMS performed in the field by paramedics identifies LVO and CSC-appropriate patients with good accuracy. The LAMS performs comparably or better than more extended prehospital scales and the full National Institutes of Health Stroke Scale.

Modulation of the anticonvulsant effect of swim stress by agmatine.

Agmatine is an endogenous l-arginine metabolite with neuroprotective effects in the stress-response system. It exerts anticonvulsant effects against several seizure paradigms. Swim stress induces an anticonvulsant effect by activation of endogenous antiseizure mechanisms. In this study, we investigated the interaction of agmatine with the anticonvulsant effect of swim stress in mice on pentylenetetrazole (PTZ)-induced seizure threshold. Then we studied the involvement of nitric oxide (NO) pathway and endogenous opioid system in that interaction. Swim stress induced an anticonvulsant effect on PTZ seizures which was opioid-independent in shorter than 1-min swim durations and opioid-dependent with longer swims, as it was completely reversed by pretreatment with naltrexone (NTX) (10mg/kg), an opioid receptor antagonist. Agmatine significantly enhanced the anticonvulsant effect of opioid-independent shorter swim stress, in which a combination of subthreshold swim stress duration (45s) and subeffective dose of agmatine (1mg/kg) revealed a significantly higher seizure threshold compared with either one. This effect was significantly reversed by NO synthase inhibitor NG-nitro-l-arginine (L-NAME (Nω-Nitro-L-arginine methyl ester), 5mg/kg), suggesting an NO-dependent mechanism, and was unaffected by NTX (10mg/kg), proving little role for endogenous opioids in the interaction. Our data suggest that pretreatment of animals with agmatine acts additively with short swim stress to exert anticonvulsant responses, possibly by mediating NO pathway.

Atrial Fibrillation Predictors on Mobile Cardiac Telemetry in Cryptogenic Ischemic Stroke.

BACKGROUND AND PURPOSE: The objective of our study was to evaluate magnetic resonance imaging (MRI) and echocardiographic characteristics that would identify patients with cryptogenic ischemic stroke (IS) and transient ischemic attack (TIA) who subsequently developed paroxysmal atrial fibrillation (PAF) on mobile cardiac outpatient telemetry (MCOT). METHODS: All patients with cryptogenic IS or TIA seen at the Emory University Hospital and Emory University Hospital Midtown from January 1, 2009, to June 30, 2013, who underwent MCOT were included in this analysis. Location (cortical, high subcortical, or neither) of current and prior strokes on MRI and left atrial (LA) functional and anatomical echocardiographic parameters were evaluated to determine their association with subsequent detection of PAF. RESULTS: Of 132 patients, 17 (13%) had evidence of newly diagnosed PAF on MCOT (mean duration of monitoring = 25 days). The presence (vs absence) of ≥1 cortical infarct on baseline MRI was a significant predictor of identifying PAF (odds ratio: 5.2, 95% confidence interval: 1.3-19; P = .01). On baseline echocardiography, patients who had PAF (vs non-PAF) had significantly higher mean LA diameters (4.2 vs 3.7 cm, P = .03) and lower tissue Doppler velocity (a'; 5.5 vs 13.5 cm/s, P = .03). In receiver operating characteristic analysis, the ratio of LA volume index to the septal Doppler velocity (LAVI/a') of >4.6 was associated with a higher likelihood of PAF. Combining MRI with echocardiographic variables did not improve the predictive ability beyond echocardiography alone. CONCLUSION: Although the presence of cortical-based infarcts on MRI in patients with cryptogenic IS or TIA increases the likelihood of detecting PAF on MCOT, LA functional and anatomic parameters alone best predicted which patients subsequently had PAF.

Endovascular Therapy in Strokes with ASPECTS 5-7 May Result in Smaller Infarcts and Better Outcomes as Compared to Medical Treatment Alone.

INTRODUCTION: Intra-arterial therapy (IAT) for large vessel occlusion strokes (LVOS) has been increasingly utilized. The benefit of IAT in patients with midrange Alberta Stroke Program Early Computed Tomography Score (ASPECTS) remains to be established. MATERIALS AND METHODS: This was a retrospective analysis of LVOS with ASPECTS 5-7 treated with IAT (n = 86) or medical therapy alone (intravenous tissue plasminogen activator; n = 15) at two centers from 2009 to 2012. Definitions were as follows: symptomatic intracranial hemorrhage = any parenchymal hematoma; successful reperfusion = mTICI ≥2b; good and acceptable outcomes = 90-day mRS 0-2 and 0-3, respectively. Final infarct volumes (FIV) were calculated based on 24-hour CT/MRI scans. RESULTS: Mean age (67 ± 14 vs. 67 ± 19 years) and baseline NIHSS (20 ± 5 vs. 20 ± 6) were similar in the two groups. Successful reperfusion was achieved in 58 (67%) IAT patients. Symptomatic and asymptomatic intracranial hemorrhage occurred in 9 (10%) and 31 (36%) IAT patients, respectively. The proportion of 90-day good and acceptable outcomes was 20 (17/86) and 33% (28/86), respectively. Successful IAT reperfusion was associated with smaller FIV (p = 0.015) and higher rates of good (p = 0.01) and acceptable (p = 0.014) outcomes. There was a strong trend towards a higher hemicraniectomy requirement in medically as compared to endovascularly treated patients (20 vs. 6%; p = 0.06) despite similar in-hospital mortality. The median FIV was significantly lower with IAT versus medical therapy [80 ml (interquartile range, 38-122) vs. 190 ml (121-267); p = 0.015]. CONCLUSIONS: Despite a relatively low probability of achieving functional independence, IAT in LVOS patients with ASPECTS 5-7 appears to result in lower degrees of disability and may lessen the need for hemicraniectomy. Therefore, it may be a reasonable option for patients and families who favor a shift from severe to moderate disability.

DWI Lesion Patterns Predict Outcome in Stroke Patients with Thrombolysis.

BACKGROUND: Lesion patterns may predict prognosis after acute ischemic stroke within the middle cerebral artery (MCA) territory; yet it remains unclear whether such imaging prognostic factors are related to patient outcome after intravenous thrombolysis. AIMS: The aim of this study is to investigate the clinical outcome after intravenous thrombolysis in acute MCA ischemic strokes with respect to diffusion-weighted imaging (DWI) lesion patterns. METHODS: Consecutive acute ischemic stroke cases of the MCA territory treated over a 7-year period were retrospectively analyzed. All acute MCA stroke patients underwent a MRI scan before intravenous thrombolytic therapy was included. DWI lesions were divided into 6 patterns (territorial, other cortical, small superficial, internal border zone, small deep, and other deep infarcts). Lesion volumes were measured by dedicated imaging processing software. Favorable outcome was defined as modified Rankin scale (mRS) of 0-2 at 90 days. RESULTS: Among the 172 patients included in our study, 75 (43.6%) were observed to have territorial infarct patterns or other deep infarct patterns. These patients also had higher baseline NIHSS score (p < 0.001), a higher proportion of large cerebral artery occlusions (p < 0.001) and larger infarct volume (p < 0.001). Favorable outcome (mRS 0-2) was achieved in 89 patients (51.7%). After multivariable analysis, groups with specific lesion patterns, including territorial infarct and other deep infarct pattern, were independently associated with favorable outcome (OR 0.40; 95% CI 0.16-0.99; p = 0.047). CONCLUSIONS: Specific lesion patterns predict differential outcome after intravenous thrombolysis therapy in acute MCA stroke patients.

Treatment and Outcome of Thrombolysis-Related Hemorrhage: A Multicenter Retrospective Study.

IMPORTANCE: Treatments for symptomatic intracerebral hemorrhage (sICH) are based on expert opinion, with limited data available on efficacy. OBJECTIVE: To better understand the natural history of thrombolysis-related sICH, with a focus on the efficacy of various treatments used. DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective study between January 1, 2009, and April 30, 2014, at 10 primary and comprehensive stroke centers across the United States. Participants were all patients with sICH, using the definition by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), which included a parenchymal hematoma type 2 and at least a 4-point increase in the National Institutes of Health Stroke Scale score. MAIN OUTCOMES AND MEASURES: The primary outcome was in-hospital mortality, and the secondary outcome was hematoma expansion, defined as a 33% increase in the hematoma volume on follow-up imaging. RESULTS: Of 3894 patients treated with intravenous recombinant tissue plasminogen activator (rtPA) within 4½ hours after symptom onset of ischemic stroke, 128 (3.3%) had sICH. The median time from initiation of rtPA therapy to sICH diagnosis was 470 minutes (range, 30-2572 minutes), and the median time from diagnosis to treatment of sICH was 112 minutes (range, 12-628 minutes). The in-hospital mortality rate was 52.3% (67 of 128), and 26.8% (22 of 82) had hematoma expansion. In the multivariable models, code status change to comfort measures after sICH diagnosis was the sole factor associated with increased in-hospital mortality (odds ratio, 3.6; 95% CI, 1.2-10.6). Severe hypofibrinogenemia (fibrinogen level, <150 mg/dL) was associated with hematoma expansion, occurring in 36.3% (8 of 22) of patients without hematoma expansion vs in 25.0% (15 of 60) of patients with hematoma expansion (P = .01), highlighting a role for cryoprecipitate in reversing rtPA coagulopathy. CONCLUSIONS AND RELEVANCE: In this study, treatment of postthrombolysis sICH did not significantly reduce the likelihood of in-hospital mortality or hematoma expansion. Shortening the time to diagnosis and treatment may be a key variable in improving outcomes of patients with sICH.

Initial experience with upfront arterial and perfusion imaging among ischemic stroke patients presenting within the 4.5-hour time window.

BACKGROUND: Although perfusion imaging is being evaluated as a tool to select acute ischemic stroke patients who are most likely to benefit from reperfusion therapies beyond the standard time windows, there are limited data on the utility of perfusion imaging within the intravenous (IV) thrombolytic time window. METHODS: A new stroke imaging protocol was initiated at Emory University Hospital including computed tomographic angiography (CTA) and computed tomographic perfusion (CTP). All patients presenting within 4.5 hours from last known normal time with suspected stroke were prospectively identified. Impact of CTA and CTP on the clinical management was recorded prospectively by stroke team members. RESULTS: During the study period, 87 patients met eligibility criteria for the CTA/CTP protocol, of which 83 (95%) underwent this upfront comprehensive imaging protocol and 30 (34%) received IV thrombolytics. Overall, stroke team members reported that CTA and/or CTP aided their clinical management in 39 (47%) cases, including aiding in identification of a nonstroke diagnosis (n = 18), triage to the neurologic intensive care unit (n = 9), early triage to endovascular therapy (n = 4), and initiation of IV thrombolytic for low National Institutes of Health Stroke Scale score with large vessel occlusion (n = 3). Door to needle time ≤60 minutes was achieved in only 18% of patients receiving IV thrombolysis during the study period, but had improved to 44% in the subsequent 6-month period. CONCLUSIONS: An upfront CTA/CTP protocol aided stroke team decision-making in nearly half of cases. Implementation of a CTA/CTP protocol was associated with a learning curve of 6 months before door to needle time ≤60 minutes returned to similar rates as the pre-CTA/CTP protocol.

Comparison of final infarct volumes in patients who received endovascular therapy or intravenous thrombolysis for acute intracranial large-vessel occlusions.

IMPORTANCE: Studies comparing the efficacy of intra-arterial therapy (IAT) and medical therapy in reducing final infarct volume (FIV) in intracranial large-vessel occlusions (ILVOs) are lacking. OBJECTIVES: To assess whether patients with ILVOs who received IAT have smaller FIVs than patients who received either intravenous tissue plasminogen activator therapy (IVT) or no reperfusion therapy (NRT) and to determine a National Institutes of Health Stroke Scale (NIHSS) threshold score that identifies patients most likely to benefit from IAT. DESIGN: Retrospective cohort study of patients with ILVOs between 2009 and 2011. SETTING: Two large-volume stroke centers. PARTICIPANTS: Adults with anterior circulation ILVOs who presented within 360 minutes from the time last seen as normal. Patients with isolated extracranial occlusions were not included. EXPOSURE: Intra-arterial therapy, IVT, or NRT. MAIN OUTCOMES AND MEASURES: Final infarct volumes, rates of acceptable outcome defined as a modified Rankin Scale score of 0 to 3 at hospital discharge, and NIHSS threshold scores. RESULTS: A total of 203 consecutive patients with ILVOs were evaluated. Baseline characteristics were similar among the 3 groups. The median infarct volume was significantly smaller for the IAT group (42 cm3) than for the IVT group (109 cm3; P = .001) or the NRT group (110 cm3; P < .01). A higher magnitude of infarct volume reduction in more proximal occlusions was noted in the IAT group compared with the IVT and NRT groups combined: internal carotid artery terminus (75 vs 190 cm3; P < .001), M1 middle cerebral artery (39 vs 109 cm3; P = .004), and M2 middle cerebral artery (33 vs 59 cm3; P = .04) occlusions. Patients were stratified based on NIHSS score at presentation (8-13, 14-19, and ≥20). For patients with an NIHSS score of 14 or higher at presentation, IAT significantly reduced FIV (46 cm3 with IAT vs 149 cm3 with IVT or NRT; P < .001) compared with patients with an NIHSS score of 8 to 13 (22 cm3 with IAT vs 44 cm3 with IVT or NRT; P = .40). Patients with an NIHSS score of 14 or higher who received IAT appear to benefit most from IAT. CONCLUSIONS AND RELEVANCE: Our data suggest a greater reduction of FIV with IAT compared with either IVT or NRT. Moreover, patients with an NIHSS score of 14 or higher may be the best candidates for endovascular reperfusion therapy.

Alpha-synuclein transgenic mice display age-related slowing of gastrointestinal motility associated with transgene expression in the vagal system.

Gastrointestinal (GI) dysfunction is the one of the most common non-motor symptoms of Parkinson's disease (PD) and occurs in nearly every patient afflicted with this common neurodegenerative disorder. While parkinsonian motor symptoms are caused by degeneration of dopamine neurons in the midbrain substantia nigra, the neurological localization of non-motor symptoms in PD is not known. In this study, we examined a transgenic mouse model of PD in which mutant (A53T) human α-synuclein was expressed under control of the prion promoter (AS mice). We found that gastrointestinal expression of human α-synuclein in this transgenic line was limited to efferent fibers projecting from the dorsal motor nucleus of the vagus nerve (DMV) to the enteric nervous system (ENS). Older transgenic mice had a lower density of human α-synuclein expression in the GI tract, suggesting an age-related disruption of efferent vagal fibers in this model. At the same time, mice developed age-related declines in stool frequency and gastric emptying consistent with those seen in human PD. These behavioral and neuropathological patterns parallel those seen in PD patients and suggest the DMV as a target for further investigation into causes for GI neuropathology and symptomatology in parkinsonism.

Acute stroke: techniques and results with the Merci retriever.

Acute ischemic stroke is one of the most prominent causes of death and disability in the modern world. Despite extensive research, the only Food and Drug Administration-approved pharmacologic treatment is intravenous recombinant tissue plasminogen activator (rt-PA). Although reperfusion remains the most robust predictor of clinical outcome, rt-PA has been linked to low recanalization rates in large-vessel occlusion. Endovascular techniques have been developed over past decade with several theoretic advantages over intravenous rt-PA alone, including longer treatment windows and higher recanalization rates in large-vessel occlusions. The Merci retriever thrombectomy device was approved by the Food and Drug Administration in 2004 for removing thrombus in acute ischemic stroke. In this article, we review the indications for acute stroke endovascular treatment with the Merci retriever as well as the involved techniques and the results of research studies.

Stenting of complete vertebral artery ostial occlusion in a patient with medically refractory vertebrobasilar ischemia.

The case history is described of a man in his late 50s who presented with recurrent vertebrobasilar ischemic events despite maximal medical treatment in the setting of a complete left vertebral artery ostial occlusion. The complete occlusion was successfully treated with a drug-eluting stent. The patient has been symptom-free for 6 months. Stenting of vertebral artery ostial occlusion is technically feasible in well-selected cases.

Neurochemical phenotypes of myenteric neurons in the rhesus monkey.

Understanding the neurochemical composition of the enteric nervous system (ENS) is critical for elucidating neurological function in the gastrointestinal (GI) tract in health and disease. Despite their status as the closest models of human neurological systems, relatively little is known about enteric neurochemistry in nonhuman primates. We describe neurochemical coding of the enteric nervous system, specifically the myenteric plexus, of the rhesus monkey (Macaca mulatta) by immunohistochemistry and directly compare it to human tissues. There are considerable differences in the myenteric plexus along different segments of the monkey GI tract. While acetylcholine neurons make up the majority of myenteric neurons in the stomach (70%), they are a minority in the rectum (47%). Conversely, only 22% of gastric myenteric neurons express nitric oxide synthase (NOS) compared to 52% in the rectum. Vasoactive intestinal peptide (VIP) is more prominent in the stomach (37%) versus the rest of the GI tract (≈10%), and catecholamine neurons are rare (≈1%). There is significant coexpression of NOS and VIP in myenteric neurons that is more prominent in the proximal GI tract. Taken as a whole, these data provide insight into the neurochemical anatomy underlying GI motility. While overall similarity to other mammalian species is clear, there are some notable differences between the ENS of rhesus monkeys, humans, and other species that will be important to take into account when evaluating models of human diseases in animals.

Delayed gastric emptying and enteric nervous system dysfunction in the rotenone model of Parkinson's disease.

Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility in PD include early satiety and weight loss from delayed gastric emptying and constipation from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the parkinsonian neurotoxin and mitochondrial complex I inhibitor rotenone causes delayed gastric emptying and enteric neuronal dysfunction when administered chronically to rats in the absence of major motor dysfunction or CNS pathology. When examined 22-28 days after initiation of rotenone infusion by osmotic minipump (3 mg/kg/day), 45% of rotenone-treated rats had a profound delay in gastric emptying. Electrophysiological recording of neurally-mediated muscle contraction in isolated colon from rotenone-treated animals confirmed an enteric inhibitory defect associated with rotenone treatment. Rotenone also induced a transient decrease in stool frequency that was associated with weight loss and decreased food and water intake. Pathologically, no alterations in enteric neuron numbers or morphology were apparent in rotenone-treated animals. These results suggest that enteric inhibitory neurons may be particularly vulnerable to the effects of mitochondrial inhibition by parkinsonian neurotoxins and provide evidence that parkinsonian gastrointestinal abnormalities can be modeled in rodents.

Seizure susceptibility alteration following reversible cholestasis in mice: Modulation by opioids and nitric oxide.

There is an increasing body of evidence that the central nervous system is affected by cholestatic liver disorders. Cholestasis has been shown to result in a decreased seizure propensity which is believed to be mediated by an increased opioidergic tone and nitric oxide (NO) signaling pathway. In this study, we used a reversible chemically-induced cholestasis model in mice to investigate the changes in seizure susceptibility. The cholestasis was induced by intragastric administration of alpha-naphthylisothiocyanate (ANIT) (100 mg/kg) or vehicle (corn oil). The threshold to generalized clonic seizures induced by timed intravenous infusion of pentylenetetrazole (PTZ) was used as an index of seizure propensity. The role of opioid receptors and NO pathway in the changes of seizure threshold, and the responsiveness to the anticonvulsant effect of opioid agonist, morphine, during and after the resolution of cholestasis was studied in this reversible paradigm of cholestatic disease. A significant increase in cholestasis-related biochemical markers as well as in clonic seizure threshold was observed; it was maximal at day 3 after cholestasis induction and slowly decreased to normal thereafter. Seizure threshold rise was inhibited by chronic administration of the opioid antagonist naltrexone or acute administration of N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO production. Co-administration of subeffective doses of L-NAME and naltrexone showed an additive effect. Injection of an anticonvulsant dose of morphine on day 7 after cholestasis induction did not increase seizure threshold, suggestive of a downregulation of receptors even after cholestasis resolution. These data shows that ANIT-induced cholestasis leads to a reversible increased resistance to PTZ-induced seizures through an opioid/NO-mediated pathway, and is probably accompanied by downregulation of opioid receptors.

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease.

Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility include early satiety and nausea from delayed gastric emptying, bloating from poor small bowel coordination, and constipation and defecatory dysfunction from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the prototypical parkinsonian neurotoxin, MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), is a selective dopamine neuron toxin in the enteric nervous system (ENS). When examined 10 days after treatment, there was a 40% reduction of dopamine neurons in the ENS of C57Bl/6 mice administered MPTP (60 mg/kg). There were no differences in the density of cholinergic or nitric oxide neurons. Electrophysiological recording of neural-mediated muscle contraction in isolated colon from MPTP-treated animals confirmed a relaxation defect associated with dopaminergic degeneration. Behaviorally, MPTP induced a transient increase in colon motility, but no changes in gastric emptying or small intestine transit. These results provide the first comprehensive assessment of gastrointestinal pathophysiology in an animal model of PD. They provide insight into the impact of dopaminergic dysfunction on gastrointestinal motility and a benchmark for assessment of other PD model systems.

The synergistic anticonvulsant effect of agmatine and morphine: possible role of alpha 2-adrenoceptors.

Recent demonstrations of the anticonvulsant properties of agmatine suggest it may be considered as a potential adjunct for protection against seizure. We investigated the possibility of an additive anticonvulsant effect between low doses of agmatine and morphine. The thresholds for the clonic seizures induced by the intravenous administration of gamma-aminobutyric acid (GABA)-antagonist, pentylenetetrazole (PTZ) were assessed in mice. Morphine at lower doses (1-3mg/kg) increased and at higher doses (30, 60 mg/kg) decreased the seizure threshold. Pretreatment with a per se non-effective dose of agmatine (1mg/kg) potentiated the anticonvulsant effect of morphine. The combination of subeffective doses of agmatine and morphine led to potent anticonvulsant effects. The pro-convulsant effect of morphine was attenuated by agmatine. Yohimbine with a dose (1mg/kg) incapable of affecting seizure threshold reversed the effect of agmatine on both anticonvulsant and pro-convulsant effects of morphine. These results suggest that agmatine potentiates the anticonvulsant effect of morphine and alpha 2-adrenoceptors may be involved in this effect.