Vincamine as an agonist of G-protein-coupled receptor 40 effectively ameliorates diabetic peripheral neuropathy in mice.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, which has yet no curable medication. Neuroinflammation and mitochondrial dysfunction are tightly linked to DPN pathology. G-protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic ß-cells, but also in spinal dorsal horn and dorsal root ganglion (DRG) neurons, regulating neuropathic pain. We previously have reported that vincamine (Vin), a monoterpenoid indole alkaloid extracted from Madagascar periwinkle, is a GPR40 agonist. In this study, we evaluated the therapeutic potential of Vin in ameliorating the DPN-like pathology in diabetic mice. Both STZ-induced type 1 (T1DM) and db/db type 2 diabetic (T2DM) mice were used to establish late-stage DPN model (DPN mice), which were administered Vin (30 mg·kg-1·d-1, i.p.) for 4 weeks. We showed that Vin administration did not lower blood glucose levels, but significantly ameliorated neurological dysfunctions in DPN mice. Vin administration improved the blood flow velocities and blood perfusion areas of foot pads and sciatic nerve tissues in DPN mice. We demonstrated that Vin administration protected against sciatic nerve myelin sheath injury and ameliorated foot skin intraepidermal nerve fiber (IENF) density impairment in DPN mice. Moreover, Vin suppressed NLRP3 inflammasome activation through either ß-Arrestin2 or ß-Arrestin2/IκBα/NF-κB signaling, improved mitochondrial dysfunction through CaMKKß/AMPK/SIRT1/PGC-1α signaling and alleviated oxidative stress through Nrf2 signaling in the sciatic nerve tissues of DPN mice and LPS/ATP-treated RSC96 cells. All the above-mentioned beneficial effects of Vin were abolished by GPR40-specific knockdown in dorsal root ganglia and sciatic nerve tissues. Together, these results support that pharmacological activation of GPR40 as a promising therapeutic strategy for DPN and highlight the potential of Vin in the treatment of this disease.

Disease-Modifying Effects of Vincamine Supplementation in Drosophila and Human Cell Models of Parkinson's Disease Based on DJ-1 Deficiency.

Parkinson's disease (PD) is an incurable neurodegenerative disorder caused by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Current therapies are only symptomatic and are not able to stop or delay its progression. In order to search for new and more effective therapies, our group carried out a high-throughput screening assay, identifying several candidate compounds that are able to improve locomotor ability in DJ-1ß mutant flies (a Drosophila model of familial PD) and reduce oxidative stress (OS)-induced lethality in DJ-1-deficient SH-SY5Y human cells. One of them was vincamine (VIN), a natural alkaloid obtained from the leaves of Vinca minor. Our results showed that VIN is able to suppress PD-related phenotypes in both Drosophila and human cell PD models. Specifically, VIN reduced OS levels in PD model flies. Besides, VIN diminished OS-induced lethality by decreasing apoptosis, increased mitochondrial viability, and reduced OS levels in DJ-1-deficient human cells. In addition, our results show that VIN might be exerting its beneficial role, at least partially, by the inhibition of voltage-gated sodium channels. Therefore, we propose that these channels might be a promising target in the search for new compounds to treat PD and that VIN represents a potential therapeutic treatment for the disease.

ALK and ERBB2 Protein Inhibition is Involved in the Prevention of Lung Cancer Development by Vincamine.

BACKGROUND: According to the WHO report of 2022, 2.21 million new cases and 1.80 million deaths were reported for lung cancer in the year 2020. Therefore, there is an urgent need to explore novel, safe, and effective therapeutic interventions for lung cancer. OBJECTIVE: To find the potential targets of vincamine using a network pharmacology approach and docking studies and to evaluate the anti-cancer effect of vincamine on A549 cell line. METHODS: Hence, in the present study, we explored the anti-cancer potential of vincamine by using network pharmacology, molecular docking, and in vitro approaches. Network pharmacology demonstrated that the most common targets of vincamine are G-protein coupled receptors, cytosolic proteins, and enzymes. Among these targets, two targets, ALK and ERBB2 protein, were common between vincamine and non-small cell lung cancer. RESULTS: We discovered a link between these two targets and their companion proteins, as well as cancer-related pathways. In addition, a docking investigation between the ligand for vincamine and two targeted genes revealed a strong affinity toward these targeted proteins. Further, the in vitro study demonstrated that vincamine treatment for 72 h led to dosedependent (0-500 µM) cytotoxicity on the A549 lung cancer cell line with an IC50 value of 291.7 µΜ. The wound-healing assay showed that vincamine treatment (150 and 300 µM) significantly inhibited cell migration and invasion. Interestingly, acridine orange/ethidium bromide dual staining demonstrated that vincamine treatment induces apoptosis in A549 cells. Additionally, the dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay showed an increased level of reactive oxygen species (ROS) after the vincamine treatment, indicating ROS-mediated apoptosis in A549 cells. CONCLUSION: Altogether, based on our findings, we hypothesize that vincamine-induced apoptosis of lung cancer cells via ALK and ERBB2 protein modulation may be an attractive futuristic strategy for managing lung cancer in combination with chemotherapeutic agents to obtain synergistic effects with reduced side effects.

Screening potential anaphylactoid components in vinpocetine injection using a high expression Mas-related G-protein-coupled receptor X2 cell membrane chromatography.

Vinpocetine injection is often used in clinical treatment of acute cardiovascular and cerebrovascular diseases. However, it was reported that vinpocetine injection caused allergic reactions in clinical use; therefore, its safety needs urgent attention. Until now, research on its sensitization is rarely reported. Here, the components contained in three vinpocetine injections were examined. It was found that besides vinpocetine, the synthetic raw material vincamine, the excipients benzyl alcohol and ethyl p-toluenesulfonate, and the impurities A, B, C, and D, which are excipients specified in the European Pharmacopoeia, were also present in them. Then the Mas-related G-protein-coupled receptor X2 (MRGPRX2)-HEK293 cell membrane chromatography was used to investigate the affinity of them with MRGPRX2 and found that vinpocetine, vincamine, and impurities A, B, C, and D bind to MRGPRX2. Afterwards, these compounds were further used to investigate the local sensitization ability in vivo. The results showed that vinpocetine, vincamine, and impurity C could induce swelling of the paw and decrease body temperature in mice, but only impurity C could cause local skin mast cell degranulation and serum histamine release increase. In vitro, the results also indicated that impurity C could increase intracellular [Ca2+ ] in MRGPRX2-HEK293 cells, whereas vinpocetine and vincamine did not. Therefore, the impurity C was the potential anaphylactoid component in vinpocetine injection, which may be one of the reasons for the occurrence of allergic reactions in the clinical use of vinpocetine injection. This work provides evidence on the sensitization of impurity C and also contributes to promoting the clinical safety of vinpocetine injection.

Vincamine, an active constituent of Vinca rosea ameliorates experimentally induced acute lung injury in Swiss albino mice through modulation of Nrf-2/NF-κB signaling cascade.

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is one of the leading pulmonary inflammatory disorders causing significant morbidity and mortality. Vincamine is a novel phytochemical with promising anti-inflammatory properties. In the current work, the protective effect of vincamine was studied in vitro (Raw 264.7 macrophages) and in vivo against lipopolysaccharide (LPS) induced ALI in Swiss albino mice. Vincamine significantly reduced nitrite and TNF-α release from the LPS stimulated macrophages and increased the levels of IL-10, indicating potent anti-inflammatory effects. It was observed that vincamine at the dose of 40 mg/kg, significantly reduced LPS induced inflammatory cell count in blood and in bronchoalveolar lavage (BAL) fluid. Further, vincamine exerted potent suppression of inflammation by reducing the expression of proinflammatory cytokines, while significantly increased (p < 0.001) the expression of anti-inflammatory cytokine (IL-10 and IL-22). Interestingly, histological changes were reversed in vincamine treated groups in a dose-dependent manner. Immunohistochemical analysis revealed significantly enhanced expression of NF-κB, TNF-α and COX-2 while reduced expression of Nrf-2 in disease control group, which were significantly (p < 0.001) ameliorated by vincamine. We, to the best of our knowledge, report for the first time that vincamine possesses protective potential against LPS induced inflammation and oxidative stress, possibly by inhibiting the NF-κB cascade, while positively regulating the Nrf-2 pathway. These findings are of potential relevance for COVID-19 management concerning the fact that lung injury and ARDS are its critical features.

Efficacy of Vincamine treatment in a rat model of anterior ischemic optic neuropathy.

Non-arteritic anterior ischemic optic neuropathy (NAION) is characterized by the progressive and irreversible death of retinal ganglion cells (RGCs) which is caused by the insufficient blood supply to the optic nerve (ON) head. At present, hormone therapy is used to reduce optic edema, followed by nerve nutrition therapy to protect the ON. However, no surgical or medical therapy has proven to be beneficial consistently in treating NAION. Vincamine is an alkaloid extracted from the Apocynaceae Vinca plant. Vincamine and its derivatives acting as cerebral vasodilators can easily cross the blood-brain barrier, improve the metabolism of ischemic tissue and protect the neuron. In this study, we aimed to investigate the potential neuroprotection of Vincamine in the photodynamic induced rat model of NAION (rAION), to evaluate its effects and possible mechanisms. We found that Vincamine can rescue RGC death and reduce the number of apoptotic cells. The protection of Vincamine might play through the PI3K/Akt/eNOS signaling pathway. Therefore, Vincamine can be an effective therapy method for NAION.

Antidiabetic, antihyperlipidemic and antioxidant effect of Vincamine, in streptozotocin-induced diabetic rats.

Diabetes mellitus is the most common endocrine disorder characterized by hyperglycemia resulting from defects in insulin secretion or insulin action. The present study was designed to investigate the antidiabetic effects of vincamine, one of the monoterpenoid indole alkaloid, in streptozotocin-induced diabetic rat model. Diabetes was induced in rats by an intraperitoneal injection of streptozotocin (40 mg/kg bw). Vincamine 20 and 30 mg/kg.bw were administrated orally as a single dose per day to the diabetic rats for 30 days. The vehicle control group received 0.5% dimethyl sulfoxide for the same duration. After 30 days of treatment, fasting blood glucose, glycosylated haemoglobin, total cholesterol, triglyceride, low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol levels were significantly increased, whereas, body weight, plasma insulin, high-density lipoprotein cholesterol, antioxidant enzymes and reduced glutathione were markedly decreased in diabetic rats. Treatment with vincamine significantly restored these parameters to the normal level. The protective effect of vincamine was compared with glibenclamide, a well-known hypoglycemic drug. Our results clearly suggest that vincamine exhibit hypoglycemic, hypolipidemic and antioxidant activity. The anti-diabetic effect of vincamine was comparable to the protective effect of glibenclamide, suggesting its potential as a natural anti-diabetic compound with therapeutic benefits.

Alpneumines A-H, new anti-melanogenic indole alkaloids from Alstonia pneumatophora.

Eight new indole alkaloids, alpneumines A-H (1-8) were isolated from the Malaysian Alstonia pneumatophora (Apocynaceae) and their structures were determined by MS and 2D NMR spectroscopic methods. Alpneumines E and G (5 and 7), vincamine, and apovincamine showed anti-melanogenesis in B16 mouse melanoma cells.

WITHDRAWN: Interventions for normal tension glaucoma.

BACKGROUND: Normal tension glaucoma is a clinical condition in which the optic nerve is pathologically excavated and the visual field is disturbed. Nevertheless it has been assumed that intraocular pressure plays a role in the progression of visual field defects in this disease, but other, mainly vascular factors, have been discussed as well. OBJECTIVES: The objective of this review is to assess the effects of medical and surgical treatments for normal tension glaucoma. SEARCH STRATEGY: Trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group trials register), MEDLINE, EMBASE and BIOSIS Previews. Bibliographies of identified trials were searched to find additional trials. In addition, investigators and pharmaceutical companies were contacted. Date of last search: January 2001. SELECTION CRITERIA: This review includes randomised controlled trials in which medical or surgical interventions were compared to no treatment, placebo or other treatment in people with normal tension glaucoma. DATA COLLECTION AND ANALYSIS: Data were extracted by two reviewers and results were compared for differences. Discrepancies were resolved by discussion. The heterogeneity of interventions, follow-up periods and outcomes did not allow for statistical combinations of the study results. MAIN RESULTS: According to the selection criteria on visual field loss, eight studies were included in this review. Only three studies focussed on patient relevant outcomes. In one trial a beneficial effect of lowering intraocular pressure was found, but only if data were corrected for cataract development. In two small studies a beneficial effect on visual field loss of brovincamine, a calcium antagonist was reported. AUTHORS' CONCLUSIONS: In one study the effect of intraocular pressure lowering on visual field outcome was only significant when data were corrected for cataract development. The results for calcium antagonists are promising, but larger trials have to be performed. Studies that focussed on reduction of intraocular pressure or haemodynamic variables are not necessarily relevant for the outcome in people with normal tension glaucoma.

Interventions for normal tension glaucoma.

BACKGROUND: Normal tension glaucoma is a clinical condition in which the optic nerve is pathologically excavated and the visual field is disturbed. Nevertheless it has been assumed that intraocular pressure plays a role in the progression of visual field defects in this disease, but other, mainly vascular factors, have been discussed as well. OBJECTIVES: The objective of this review is to assess the effects of medical and surgical treatments for normal tension glaucoma. SEARCH STRATEGY: Trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group trials register), MEDLINE, EMBASE and BIOSIS Previews. Bibliographies of identified trials were searched to find additional trials. In addition, investigators and pharmaceutical companies were contacted. Date of last search: January 2001. SELECTION CRITERIA: This review includes randomised controlled trials in which medical or surgical interventions were compared to no treatment, placebo or other treatment in people with normal tension glaucoma. Two reviewers independently assessed the full text copies of the possibly relevant trials. Trial quality was assessed according to the methods set out in Section 6 of the Cochrane Reviewers' Handbook (Clarke 2000). DATA COLLECTION AND ANALYSIS: Data were extracted by two reviewers and results were compared for differences. Discrepancies were resolved by discussion. The heterogeneity of interventions, follow-up periods and outcomes did not allow for statistical combinations of the study results. MAIN RESULTS: According to the selection criteria on visual field loss, eight studies were included in this review. Only three studies focussed on patient relevant outcomes. In one trial a beneficial effect of lowering intraocular pressure was found, but only if data were corrected for cataract development. In two small studies a beneficial effect on visual field loss of brovincamine, a calcium antagonist was reported. REVIEWER'S CONCLUSIONS: In one study the effect of intraocular pressure lowering on visual field outcome was only significant when data were corrected for cataract development. The results for calcium antagonists are promising, but larger trials have to be performed. Studies that focussed on reduction of intraocular pressure or haemodynamic variables are not necessarily relevant for the outcome in people with normal tension glaucoma.

[Open-angle glaucoma clinical presentation and management].

Both primary open-angle and normal-tension glaucoma belong to an identical spectrum of diseases. Clinical presentations of primary open-angle or high-tension glaucoma (POAG) and normal-tension glaucoma (NTG) were studied in an attempt to determine prognostic, clinical factors and define the appropriate management. Clinical data obtained from 826 primary open-angle and normal-tension glaucoma patients were analyzed. In addition, the results of laboratory studies, including the immunological assay of heat shock protein (hsp) and gene analyses which were undertaken to identify risk factors at the molecular level, are discussed. 1. The identified prognostic factors were disk hemorrhage, peripapillary chorioretinal atrophy (PPA), maximum intraocular pressure (IOP), the recovery rate of skin temperature after exposure to cold, family history of glaucoma, systemic systolic channel blood pressure, and oral administration of Ca(2+)-channel antagonists. 2. Disk hemorrhage was observed in 30.5% of NTG patients and 15.4% of POAG patients. Cumulative probability of hemorrhagic events was 16.9% in POAG and 38.4% in NTG patients at the end of a 14.8-year follow-up. 3. The hazard ratio of disk hemorrhage decreased with the increase of IOP(26%/5 mmHg) and was 1.46 times higher in females than in males. Disk hemorrhage was closely associated with PPA: PPA becomes greater in association with the progression of glaucomatous optic neuropathy in both POAG and NTG. No such correlation was noted in primary angle-closure glaucoma. 4. Color Doppler imaging analyses and the hourly determination of ocular perfusion pressure (OPP) indicated a difference in retrobulbar hemodynamics between OPP-mean deviation concordant and OPP-mean deviation discordant patients: a circulatory disturbance causally unrelated to OPP seems to be involved in the OPP-mean deviation discordant patients. 5. The oral administration of Ca(2+)-channel antagonists was shown to favorably influence retrobulbar hemodynamics in NTG patients. 6. Serum antigen titer to hsps(hsp 27, alpha B crystallin, human & bacterial hsp 60) was higher in both POAG and NTG patients than in normal subjects. None of the hsp-antigens was correlated to any morphometric parameters of the optic disk or any global indices of the visual field. 7. Myocilin mutation was noted in only 0.5% of POAG patients and 2.37% of NTG patients. The very low rate of occurrence precludes the value of mutation of the gene as a prognostic factor in open-angle glaucoma(OAG). 8. IOP reduction achieved by mitomycin-C trabeculectomy is effective in maintaining visual function in OAG eyes. 9. Brovincamine fumarate is effective in inhibiting the progression of glaucomatous field loss in NTG.

[A new approach to the treatment of patients with circulatory encephalopathy]. / Novyi pidkhid do likuvannia khvorykh na dystsyrkuliatornu entsefalopatiiu.

Effects were studied of vincamin and tanakan in 68 patients with stage I, II and III discirculatory encephalopathy (as per WHO classification 1981). In 52% of the patients atherosclerosis of brain vessels was associated with arterial hypertension (group I), in 48 per cent venous discirculatory encephalopathy was diagnosable against the background of arterial hypertension (group IIA-20%) and arterial hypotension (group IIB-26%). Both tanakan and vincamin were found to be effective in group I patients; however, in stage III condition their effectiveness was no better than 42 and 15% respectively, which fact might be due to organic changes in the vascular wall. Tanakan appeared to be more beneficial in group II patients since venous dystonia is considered to be the main pathogenetic link in this context, and tanakan is known to improve the venous outflow from the cranial cavity. Almost in one-third of group IIB patients vincamin worsened general health status, especially so in stage III discirculatory encephalopathy, which fact may be related to peculiar effect of the drug on the arterial link of brain blood supply.

Prevention of visual field defect progression with brovincamine in eyes with normal-tension glaucoma.

PURPOSE: A prospective investigation of the effect of brovincamine fumarate, a Ca2+-channel blocker, on visual field changes in normal-tension glaucoma (NTG). METHODS: A total of 28, age- and field-matched, patients with NTG were allocated randomly to either brovincamine fumarate (20 mg 3 times daily) or placebo (3 times daily). The patients were followed at least every 4 months for a minimum of 2.5 years, and visual field examinations were carried out at least every 6 months. The mean follow-up periods (+/-standard deviation) were 39.1 +/- 8.7 months in the brovincamine-treated group and 37.9 +/- 10.1 months in the placebo group. Stepwise discriminant analyses were performed to separate the patients who showed improvement of their visual fields from those who failed to improve in the brovincamine-treated group, and to identify factors that may determine the visual field prognosis of all patients with NTG enrolled in the study. RESULTS: In the brovincamine-treated group, six patients showed visual field improvement, whereas none showed improvement in the placebo group using the Statpac 2 linear regression analysis. Discriminant analyses identified better cold recovery rate and higher initial systolic blood pressure to be significantly contributory to a favorable outcome in the brovincamine-treated group, and the use of brovincamine, better cold recovery rate, and higher initial systolic blood pressure were identified to be significantly contributory to a favorable prognosis in all subjects. CONCLUSION: Brovincamine seems to have a favorable effect on visual field in at least some patients with NTG.

Therapeutic efficacy of vincamine in dementia.

This trial was performed to investigate the therapeutic efficacy of vincamine in the treatment of primary degenerative and vascular dementia. 152 male and female patients aged between 50 and 85 years from two psychogeriatric centers and two nursing homes were initially included in the trial and screened for eligibility. 142 patients completed the trial. Clinical diagnosis was established according to DSM-III-R criteria. Allocation of the patients to the primary degenerative dementia of the Alzheimer type (DAT) group or the multi-infarct dementia (MID) group was based on computed tomography scans, electroencephalographic findings and the Hachinski Ischemic Score. In a 12-week double-blind treatment either 30 mg vincamine or placebo was given twice daily. Confirmatory statistics included item 2 of the Clinical Global Impression (CGI), the total score of the Sandoz Clinical Assessment Geriatric (SCAG) scale, the subscale 'need for help' of the nurse's rating of geriatric patients (Beurteilungsskala für geriatrische Patienten; BGP) and the total score of the Short Cognitive Performance Test (Syndrom-Kurztest; SKT). In addition, data on tolerance and on therapy response were evaluated based on descriptive statistics. The therapeutic efficacy of vincamine was clearly demonstrated by confirmatory analysis as the drug was statistically significantly superior to placebo in all four target variables. The clinical relevance of the outcome was further underlined by the results of the responder analysis of the variables SCAG, BGP and SKT. Based on the results of this trial, it can be accepted that the therapeutic effect of vincamine is superior to placebo in patients with mild to moderate dementia of degenerative and vascular etiologies.

Effect of brovincamine on cerebral circulation and metabolism in internal carotid artery occlusion examined by positron emission tomography.

We evaluated the effect of brovincamine on the circulatory and metabolic state in the brain ischemia with internal carotid artery occlusion accompanying the 'misery perfusion syndrome'. Cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and oxygen extraction fraction (OEF) were measured by PET before and after intravenous loading of brovincamine. Brovincamine increased CBF and decreased OEF significantly on the occluded side of the hemisphere. CMRO2 did not show any remarkable changes upon brovincamine administration. It was concluded that brovincamine might be useful for increasing the hemodynamic reserve, but did not affect the metabolic state immediately after its administration.

The pharmacotherapy of focal cortical ischaemia in the mouse.

The measurement of cortical omega 3 (peripheral-type benzodiazepine binding) site densities provides an accurate index for the detection and quantification of ischaemic brain lesions following middle cerebral artery occlusion (MCAO) in mice. Here, we have used this marker to assess the neuroprotective activity of potential anti-ischaemic drugs belonging to several chemical classes. In untreated mice, the mean infarcted volume measured 96 h after unilateral coagulation of the middle cerebral artery was 27.9 +/- 4.3 mm3 (17.5% of the hemisphere volume) and omega 3 site densities (measured by incubation with 3H-PK 11195) were increased by 107.3 +/- 4.8% (cortical homogenates) or by 81% (coronal brain sections). The administration of the anti-ischaemic agent SL 82.0715 (10 mg/kg i.p.), 5 min, 6 h and 18 h after the occlusion and then twice daily until sacrifice evoked a decrease of similar magnitude (ca. 60-70%) in the volume of the infarction and in the proliferation of omega 3 sites. The constant tissue sparing effect of SL 82.0715 allowed the examination of the window of therapeutic opportunity. A significant diminution of cortical omega 3 sites was still noted when the first administration was delayed until 3 h post-occlusion. Moreover, the protective effect of SL 82.0715 was enhanced by repeated treatment for the first 36 h but not thereafter. Based on the histological, autoradiographic and homogenate binding results obtained with SL 82.0715, we studied the protective effects of several competitive and non-competitive NMDA receptor antagonists. When administered according to the above-described standard protocol, these drugs reduced omega 3 site levels in cortical homogenates from MCAO mice in a dose-dependent manner. The dose preventing by 50% the increase in omega 3 site levels (in mg/kg i.p.) and the maximal inhibition were respectively: MK-801 (0.2, 93%); TCP (1.6, 66%); kynurenate (260, 58%); ifenprodil (7.0, 58%); SL 82.0715 (1.1, 72%); CGS 19755 (46% at 10 mg/kg); dextromethorphan (46% at 30 mg/kg). In contrast, agents acting preferentially upon sigma (sigma) opiate receptors ((+)-3PPP, 1-10 mg/kg i.p. and haloperidol, 0.3-3 mg/kg i.p.) did not provide a significant protection. In general, calcium channel blockers (nimodipine, flunarizine, verapamil, perhexiline, diltiazem) were devoid of a clear neuroprotective potential when administered at non-toxic doses after the coagulation of the middle cerebral artery. Diltiazem (3 and 10 mg/kg i.p.) provided a significant protection when the first administration was performed 10 min prior to the occlusion. Limited protection was observed with adenosine A1 receptor agonists (N6-cyclohexyladenosine and 2-chloro-adenosine).(ABSTRACT TRUNCATED AT 400 WORDS)

Double tracer autoradiographic method for sequential evaluation of regional cerebral perfusion.

A new double tracer autoradiographic method for the sequential evaluation of altered regional cerebral perfusion in the same animal is presented. This method is based on the sequential injection of two tracers, 99mTc-hexamethylpropyleneamine oxime and N-isopropyl-(125I)p-iodoamphetamine. This method is validated in the assessment of brovincamine effects on regional cerebral perfusion in an experimental model of chronic brain ischemia in the rat. The drug enhanced perfusion recovery in low-flow areas, selectively in surrounding areas of infarction. The results suggest that this technique is of potential use in the study of neuropharmacological effects applied during the experiment.

[Effect of brovincamine fumarate on cerebral ischemia acutely induced by BLCL in SHRSR].

The present study was designed to clarify the effect of brovincamine fumarate (BV 26-723: BV) on the degree of cerebral ischemia acutely induced by bilateral common carotid artery ligation (BLCL) in stroke-resistant spontaneously hypertensive rats (SHRSR). BV was administered to SHRSR by intraperitoneal infusion (I.P.) of 30 mg/kg (BV 30 mg/kg group), 60 mg/kg (BV 60 mg/kg group) and 0.9% saline was similarly injected to SHRSR (control group) before and immediately after BLCL. Cerebral blood flow (rCBF) in the thalamus was measured by hydrogen clearance technique before and until 3 hr of BLCL periodically. The brain metabolites (ATP, lactate, pyruvate) were determined by the enzymatic method and the brain water content was measured by freeze-dry method 3 hr after BLCL. The histopathological changes in brain vessels were observed by scanning electron microscopy (SEM) 3 hr after BLCL. The rCBF of three groups were identical before BLCL. However, the rCBF of BV 30 mg/kg group was statistically higher than in control group until 2 hr after BLCL, and that of BV 60 mg/kg group was significantly higher even 3 hr after BLCL. In measurements of the brain metabolites after BLCL, ATP and pyruvate levels in both the BV 30 mg/kg and 60 mg/kg groups were statistically higher than the control group. And brain lactate concentrations in both the BV 30 mg/kg and 60 mg/kg groups were significantly lower than the control group. The brain water content of BV 30 mg/kg and 60 mg/kg groups were significantly lower then the control group after BLCL.(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effects of vinpocetine and structurally related drugs on the lethal consequences of hypoxia in mice.

Vinpocetine has been compared with 3 structurally related drugs for activity in protecting mice from hypoxia-induced lethality upon i.p. administration. In order of potency, vinpocetine (ED50 = 16.6 mg/kg), 1-eburnamonine (ED50 = 21.0 mg/kg), vinconate (ED50 approximately 25 mg/kg), and vincamine (ED50 = 47.0 mg/kg) increased the number of mice surviving an 80 sec exposure to 100% nitrogen gas. Furthermore, the antihypoxic effects of these drugs were not due to an induced hypothermia. All of the drugs, with the exception of vinconate, exhibited a monotonic dose-response curve and caused 100% survival at some dose. The antihypoxic effects with vinpocetine and related drugs in this model correlate with protective effects observed in animal models of cerebral ischemia and with therapeutic effects in patients with compromised cerebral blood flow. The possible mechanisms of action of these drugs are discussed.