Neuroprotective effect of Arthrospira (Spirulina) platensis against kainic acid-neuronal death.

Context Arthrospira (Spirulina) platensis (SP) is a cyanobacterium which has attracted attention because of its nutritional value and pharmacological properties. It was previously reported that SP reduces oxidative stress in the hippocampus and protects against damaging neurobehavioural effects of systemic kainic acid (KA). It is widely known that the systemic administration of KA induces neuronal damage, specifically in the CA3 hippocampal region. Objective The present study determines if the SP sub-chronic treatment has neuroprotective properties against KA. Materials and methods Male SW mice were treated with SP during 24 d, at doses of 0, 200, and 800 mg/kg, once daily, and with KA (35 mg/kg, ip) as a single dose on day 14. After the treatment, a histological analysis was performed and the number of atrophic neuronal cells in CA3 hippocampal region was quantified. Results Pretreatment with SP does not protect against seizures induced by KA. However, mortality in the SP 200 and the SP 800 groups was of 20%, while for the KA group, it was of 60%. A single KA ip administration produced a considerable neuronal damage, whereas both doses of SP sub-chronic treatment reduced the number of atrophic neurons in CA3 hippocampal region with respect to the KA group. Discussion The SP neurobehaviour improvement after KA systemic administration correlates with the capacity of SP to reduce KA-neuronal death in CA3 hippocampal cells. This neuroprotection may be related to the antioxidant properties of SP. Conclusion SP reduces KA-neuronal death in CA3 hippocampal cells.

Preclinical antitoxic properties of Spirulina (Arthrospira).

CONTEXT: Spirulina (Arthrospira) exerts a wide spectrum of pharmacological activities which are mainly attributed to its antioxidant effect. However, Spirulina has also been reported (both in preclinical and in clinical scenarios) to exhibit other bioactive effects, including an antitoxic potential. OBJECTIVE: We performed a systematic review of the literature, conducted in TOXNET, PubMed/MEDLINE, and Science Direct-Scopus; all available years were included. Searching criteria included the effects of Spirulina on experimental poisonings from arsenic, cadmium, carbon tetrachloride, deltamethrin, fluoride, hexachlorocyclohexane, iron, lead, lindane, and mercury. RESULTS: In all cases, it was established that the blue-green alga, and its isolated compounds, effectively counteracted these pollutants toxic effects on the exposed organisms. Some molecular mechanisms are proposed, although they have not been fully elucidated yet. CONCLUSION: Spirulina could be a useful coadjuvant agent within clinical practice for treatment of these or other pollutants poisonings.

A study of prevention and regression of cardiac hypertrophy with a prolactin inhibitor in a biological model of ventricular hypertrophy caused by aorto caval fistulae in rat.

BACKGROUND: The possibility of decreasing or reverting left ventricular hypertrophy and, therefore, cardiac hypertrophy (CH) is an important medical issue. The aim of the present study was to evaluate these two possibilities with a 3-week daily dose of captopril, losartan, or bromocriptine in a preventive or corrective model. METHODS: After aorto caval fistulae (ACF) surgery on adult male Wistar rats to induce CH, animals were assigned to the preventive protocol (drug treatment began immediately after surgery) or corrective protocol (hypertrophy was allowed to develop before drug treatment). After treatments, isoproterenol was administered to half of the animals to further induce CH. The groups included the passive control, the sham-operated animals, those with ACF surgery but without drug treatment, and the 3-week treatments with captopril, losartan, or the low or high dose of bromocriptine. RESULTS: Three treatments, with captopril, losartan, or the high dose of bromocriptine, significantly impeded/reverted an increase in CH-related parameters in the preventive/corrective model compared to the surgically treated group without drug treatment. The same effect was found after isoproterenol administration. The present results show an avoidance/reversion of CH with these three treatments. Better results were found with the angiotensin converting enzyme inhibitor (captopril) than with the prolactin inhibitor (bromocriptine). CONCLUSIONS: Treatments with captopril, losartan, and the high dose of bromocriptine were effective in preventing/reversing the manifestation of CH in the preventive/corrective rat models. Further studies are needed to identify the initial mediator, the key component, and the molecular events involved in the pathogenesis of CH.

Protective effect of grapefruit juice on the teratogenic and genotoxic damage induced by cadmium in mice.

In the present study, we injected pregnant mice at Day 7 of gestation with cadmium chloride (CC) (1.5 mg/kg) intraperitoneally and determined its effect on the frequency of fetal malformations at Day 17 of pregnancy. On the same day, we also determined the level of micronucleated polychromatic erythrocytes (MNPEs) and of micronucleated normochromatic erythrocytes (MNNEs) in blood cells of both the mothers and their fetuses. A significant increase in the number of malformations was found, mainly exencephaly, micrognathia, ablephary, microphthalmia, and clubfoot, as well as a significant increase in the amount of MNPEs and MNNEs. In addition, pregnant mice were administered grapefruit juice (GJ) orally from Days 0 to 17 of the experiment (from 200 to 800 µL/g) to evaluate the potential of the juice in preventing the damage induced by CC. We found a dose-dependent decrease in the number of visceral and skeletal malformations, as well as in the number of MNPEs and MNNEs, in both the mothers and their fetuses. Furthermore, we determined the level of DNA oxidation by measuring levels of the adduct 8-hydroxy-2'-deoxyguanosine, and we found a significant increase in such level induced by CC; in contrast, there was a significant decrease when we added GJ. Therefore, the observed teratogenic and genotoxic protection can probably be related with the antioxidant potential of GJ.

Activities of α-asarone in various animal seizure models and in biochemical assays might be essentially accounted for by antioxidant properties.

Anticonvulsant properties of α-asarone were studied in mice at three doses with different toxicity. The 100mg/kg dose decreased both treadmill performance and locomotor activity, caused hypothermia, and potentiated pentobarbital-induced sleep. The last two effects and no toxicity were observed at 60 and 22mg/kg, respectively. In chemical (pentylenetetrazole, picrotoxin, N-methyl-D-aspartate, pilocarpine) and electrical (maximal electroshock) seizure tests, neither seizures nor death were prevented by 60 mg/kg α-asarone which, however, exhibited protective-like effects (delay in the onset of clonic and/or tonic seizures and/or in the death of mice). Magnesium deficiency-dependent audiogenic seizures responded to non-toxic doses of α-asarone (60 mg/kg and less): 22 mg/kg protecting 50% of tested animals. Because these seizures respond to both anti-seizure and antioxidant compounds, antioxidant properties of α-asarone were studied, indicating 5 Units of superoxide dismutase-like activity per mg α-asarone. Treatment of mice by α-asarone (daily dose of 100mg/kg during 7 days) induced brain antioxidant enzymes (superoxide dismutase, glutathione peroxidase and reductase) in striatum and hippocampus and to a lesser extent in cortex. In view of recent findings about deleterious roles of chronic inflammatory/oxidant stresses in human epilepsy outcome, antioxidant and inductive properties of α-asarone are proposed to be coherent bases for traditional clinical efficacy.

Inhibitors of HMG-CoA Reductase: Current and Future Prospects.

High levels of cholesterol are a primary risk factor in the development of cardiovascular diseases. In this review, we have summarized the structural, chemical and computational aspects of hypocholesterolemic drugs, both statins and non-statins, that target enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) to block cholesterol biosynthesis.

Neuroprotective effect of alpha-asarone on spatial memory and nitric oxide levels in rats injected with amyloid-beta((25-35)).

The chemical alpha-asarone is an important active substance of the Acori graminei rhizome (AGR). It has pharmacological effects that include antihyperlipidemic, antiinflammatory, and antioxidant activity. Our aim was to study the effects alpha-asarone on nitric oxide (NO) levels in the hippocampus and temporal cortex of the rat after injection of the fraction 25-35 from amyloid-beta (Abeta((25-35))). In addition we examined the working spatial memory in an eight-arm radial maze. Our results showed a significant increase of nitrites in the hippocampus and temporal cortex of Abeta((25-35))-treated rats. Other evidence of neuronal damage was the expression of a glial-fibrillar-acid protein and a silver staining. There were impairments in the spatial memory evaluated in the eight-arm radial maze. We wanted to determine whether alpha-asarone improves the memory correlated with NO overproduction and neuronal damage caused by the injection of Abeta((25-35)) into rats. Then animals received a 16-day treatment of alpha-asarone before the Abeta((25-35)) injection. Our results show a significant decrease of nitrite levels in the hippocampus and temporal cortex, without astrocytosis and silver-staining cells, which correlates with memory improvement in the alpha-asarone-treated group. Our results suggest that alpha-asarone may protect neurons against Abeta((25-35))-caused neurotoxicity by inhibiting the effects of NO overproduction in the hippocampus and temporal cortex.

Amyloid-beta(25-35) impairs memory and increases NO in the temporal cortex of rats.

beta-Amyloid plays an important role in the neurodegeneration process of Alzheimer's disease (AD), but its neurotoxic mechanisms are not clear. It has been associated with the increase of oxidative stress and cognitive impairment because the beta-amyloid peptide 25-35 (Abeta((25-35))) has the critical neurotoxic properties of the full-length Abeta(1-42). Our present study shows the role of Abeta((25-35)) when injected into the temporal cortex on the nitric oxide pathways, 3-nitrotyrosine, neuronal death, and the spatial memory of rats 1 month after the injection. Our data showed that Abeta((25-35)) increases oxidative stress, causes neuronal damage, and decreases spatial memory in rats. Notably, the injection of the fraction Abeta((25-35)) caused an increase of nNOS and iNOS immunoreactivity in the temporal cortex and hippocampus. We demonstrated a significant increase of reactive astrocytosis, which was accompanied by neuronal damage in the temporal cortex and hippocampus of rats injected with Abeta((25-35)). These data suggest that the fraction Abeta((25-35)) injected into the temporal cortex might contribute to understanding the role of nitric oxide on the biological changes related to the neuropathological progression and the memory impairment in AD.

Effect of alpha-asarone and a derivative on lipids, bile flow and Na+/K+-ATPase in ethinyl estradiol-induced cholestasis in the rat.

Administration of ethinyl estradiol (EE), a widely used component of oral contraceptives, has been associated with impairment of bile flow and the capacity to excrete organic anions in man and experimental animals. alpha-Asarone (2,4,5-trimethoxypropenylbenzene) and 2-methoxy-4-(2-propenyl) phenoxyacetic acid (MPPA) have shown hypolipidemic effects. In addition to these effects, we decided to evaluate the properties of these compounds on EE-induced cholestasis. Wistar male rats were injected subcutaneously with 10 mg/kg of EE for 5 days; simultaneously, alpha-asarone or MPPA were also administered and appropriate controls were performed. alpha-asarone and MPPA decreased plasma and bile cholesterol. EE diminished triglycerides total, low-density lipoprotein, high-density lipoprotein and bile cholesterol. MPPA further decreased these lipid parameters. Alkaline phosphatase (an enzyme marker of cholestasis) was increased after administration of EE, but this effect was prevented significantly by alpha-asarone or MPPA administration. Bile flow was importantly decreased by EE and increased by alpha-asarone alone. Furthermore, alpha-asarone or MPPA preserved the normal bile flow in EE-treated rats. EE inhibited the activity of the Na(+)/K(+)-ATPase, while both alpha-asarone and MPPA preserved this enzyme activity. Na(+)/K(+)-ATPase is involved in Na(+)-coupled uptake of bile acids into hepatocytes and, therefore, ultimately is the driving force for the generation of bile flow. Therefore, the anticholestatic effects of alpha-asarone and MPPA, described herein by the first time, may be due to its ability to preserve ATPase activity. This enzyme is negatively regulated by membrane cholesterol, thus the hypolipidemic effects of the compounds tested may be responsible for Na(+)/K(+)-ATPase activity and bile flow maintenance.

Hypolipidaemic and antiplatelet activity of phenoxyacetic acid derivatives related to alpha-asarone.

The phenoxyacetic acid derivatives 1-6 [2-methoxy-4-(2-propenyl)phenoxyacetic acid (1); 2-methoxy-5-nitro-4-(2-propenyl)phenoxyacetic acid (2); methyl 2-methoxy-4-(2-propenyl)phenoxyacetate (3); ethyl 2-methoxy-4-(2-propenyl)phenoxyacetate (4); methyl 2-methoxy-5-nitro-4-(2-propenyl)phenoxyacetate (5); ethyl 2-methoxy-5-nitro-4-(2-propenyl)phenoxyacetate (6)] related to alpha-asarone have been reported previously as hypolipidaemic agents in diet-induced hyperlipidaemic mice. We have aimed to expand the pharmacological profile of these derivatives by investigating their hypolipidaemic activity in rats and mice under different experimental conditions. The antiplatelet activity was tested also in-vitro from blood derived from consenting healthy volunteers. In normolipidaemic rats, compounds 2, 3 and 5 at oral doses of 40 and 80 mg kg(-1) significantly decreased total cholesterol and LDL-cholesterol levels. Moreover, analogues 3 and 5 administered to hypercholesterolaemic rats at the same doses for seven days also produced a reduction in the content of these same lipoproteins. In neither case were the high-density lipoprotein cholesterol and triglyceride concentrations affected. However, practically all tested compounds were found to be hypocholesterolaemic agents, and were shown to effectively lower low-density lipoprotein cholesterol and triglyceride levels in Triton-induced hyperlipidaemic mice at oral doses of 50 and 100 mg kg(-1). In all tests, all animals appeared to be healthy throughout the experimental period in their therapeutic ranges. Triton-induced hypercholesterolaemic mice appeared to be a desirable model for this class of hypolipidaemic drugs. On the other hand, compounds 1, 2, 4 and 5 significantly inhibited ADP-induced aggregation in-vitro. These findings indicated that all of these compounds appeared to be promising for the treatment of human hyperlipidaemia and thrombotic diseases.

Spirulina maxima pretreatment partially protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity.

Spirulina is an alga that has a high nutritional value and some of its biological activities are attributed to the presence of antioxidants. Oxidative stress is involved in Parkinson's disease. This study aims at evaluating the neuroprotective role of Spirulina maxima (Sp.) against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity, used as a model of Parkinson's disease. Ninety-six male C-57 black mice were pretreated with Spirulina for 14 days (25, 50, 100, 150 or 200 mg/kg, oral), followed by three MPTP administrations (30 mg/kg, intraperitoneal, i.p.). Animals were given Sp. for 8 additional days. After the treatment, the striatal dopamine (DA) content was analysed by high performance liquid chromatography, and lipid peroxidation was studied as an index of oxidative stress. Sp. pretreatment at 150 mg/kg partially prevented (51%) the DA-depleting effect of MPTP and blocked oxidative stress. Spirulina partially prevents MPTP neurotoxicity and oxidative stress, suggesting it could be a possible alternative in experimental therapy.

Molecular docking of the highly hypolipidemic agent alpha-asarone with the catalytic portion of HMG-CoA reductase.

Docking experiments using a number of published crystal structures of HMG-CoA reductase with the potent hypocholesterolemic agent alpha-asarone are described. The results indicate that alpha-asarone binds in the enzyme's active site. The methoxy groups play a key role in the binding and probably also in its biological activity, as shown by extensive SAR studies reported for analogues of alpha-asarone. The docking results will be valuable for the structure-based design of novel hypolipidemic agents.

Germ cell mutagenicity of gamma-ethyl-gamma-phenyl-butyrolactone (EPBL) detected in the CF1 mouse-dominant lethal study.

Female and male CFI mice weighing 25-30 g were given 0, 50, 100 or 200 mg/kg of gamma-ethyl-gamma-phenyl-butyrolactone (EPBL) for 5 days intraperitoneally. In the male-dominant lethal phase, males treated with EPBL were mated with untreated females following a 7-day mating schedule with three consecutive mating events. In the female-dominant lethal phase, females treated with EPBL were caged with untreated males. The above dosages and schedule treatments were used. The incidence of pregnancy of females mated on days 1-7 and 8-14 after males were given 200 mg/kg of EPBL and of females given 200 mg/kg when mated to untreated males was decreased. Upon examining surgically exposed uteri and ovaries of pregnant females during the first phase, on gestation days 13-15, an increased incidence of pre-implantation losses with 200 mg/kg of EPBL and an increased incidence of post-implantation losses with 100 and 200 mg/kg was observed. In addition, an increased frequency of pre- and post-implantation losses was seen in females treated with 200 mg/kg. These results support the conclusion that EPBL is a germ cell mutagen and its effects are more pronounced during the post-meiotic stage.

Anticlastogenic effect of Spirulina maxima extract on the micronuclei induced by maleic hydrazide in Tradescantia.

The aim of this investigation was to determine if extracts of Spirulina maxima reduce the genotoxic damage induced by maleic hydrazide (MH) using the Tradescantia biosssay. Two types of extracts from the alga were prepared: an aqueous extract with two different concentrations, 100 and 500 mg/ml, and a second one, the extract of a 1% solution of dimethyl sulfoxide (DMSO) which corresponded to 100 mg/ml of the alga. The capacity of MH to induce micronuclei (MN) was initially established by administering 0.005, 0.01, and 0.015 mg/ml of the chemical to the Tradescantia inflorescences, and observing its effect after 24 h.The results of this experiment showed a significant MN increase with the two high concentrations tested, although no dose-response effect was observed. For the anticlastogenic assay, the extracts of Spirulina were applied to the inflorescences alone or immediately before the application of MH (0.01 mg/ml) and the induced MN were observed 24 h later. We found that none of the extracts increased the MN level with respect to the untreated plants; also, that MH more or less doubled the basal micronuclei frequency, and finally, that all tested extracts reduced the genotoxic damage caused by MH. The inhibitory indices obtained for the aqueous extracts (100 and 500 mg/ml) and for the DMSO extract were respectively 59, 85, and 56.3%. These data indicate that Spirulina is an anticlastogenic agent and suggest that it is advisable to extend studies on this matter using other biological models.

[Update on the pharmacology of Spirulina (Arthrospira), an unconventional food]. / Actualización en la farmacología de Spirulina (Arthrospira), un alimento no convencional.

Spirulina (Arthrospira), a filamentous, unicellular alga, is a cyanobacterium grown in certain countries as food for human and animal consumption. It is also used to derive additives in pharmaceuticals and foods. This alga is a rich source of proteins, vitamins, amino acids, minerals, and other nutrients. Its main use, therefore, is as a food supplement. Over the last few years, however, it has been found to have many additional pharmacological properties. Thus, it has been experimentally proven, in vivo and in vitro that it is effective to treat certain allergies, anemia, cancer, hepatotoxicity, viral and cardiovascular diseases, hyperglycemia, hyperlipidemia, immunodeficiency, and inflammatory processes, among others. Several of these activities are attributed to Spirulina itself or to some of its components including fatty acids omega-3 or omega-6, beta-carotene, alpha-tocopherol, phycocyanin, phenol compounds, and a recently isolated complex, Ca-Spirulan (Ca-SP). This paper aims to update and critically review the results published over the last few years with regards to these properties. The conclusion is that even if this cyanobacterium has been one of the most extensively studied from the chemical, pharmacological and toxicological points of view, it is still necessary to expand the research in order to have more consistent data for its possible use in human beings.

Antiviral activity of Spirulina maxima against herpes simplex virus type 2.

Spirulina has been used in a variety of practical applications in biotechnology and medical sciences. This paper presents the antiviral activity found in a hot water extract (HWE) of a commercial preparation of Spirulina maxima, studied by a microplate inhibition assay, using several viruses. The HWE inhibited the infection for: herpes simplex virus type 2 (HSV-2), pseudorabies virus (PRV), human cytomegalovirus (HCMV), and HSV-1, and the 50% effective inhibition doses (ED(50)) were 0.069, 0.103, 0.142, and 0.333 mg/ml for each virus, respectively. For adenovirus the inhibition was less than 20%, and no inhibition was found for measles virus, subacute sclerosing panencephalitis virus (SSPE), vesicular stomatitis virus (VSV), poliovirus 1 and rotavirus SA-11, at concentrations of 2 mg/ml of the HWE. The highest antiviral activity was for HSV-2, with a selectivity index of 128. The antiviral activity was not due to a virucidal effect. Herpesvirus infection was inhibited at the initial events (adsorption and penetration) of the viral cycle. To initiate the isolation and identification of the compound that exhibits the antiviral activity of S. maxima, some extracts made by using several solvents with different polarity were evaluated by microplate inhibition assay using HSV-2. The highest antiviral activity was detected in the methanol-water 3:1, which suggests that the antiviral activity is probably due to highly polar compounds.

Actualización en la farmacología de Spirulina (Arthrospira), un alimento no convencional / Update on the pharmacology of Spirulina (Arthrospira), an unconventional food

Spirulina (Arthrospira), a filamentous, unicellular alga, is a cyanobacterium grown in certain countries as food for human and animal consumption. It is also used to derive additives in pharmaceuticals and foods. This alga is a rich source of proteins, vitamins, amino acids, minerals, and other nutrients. Its main use, therefore, is as a food supplement. Over the last few years, however, it has been found to have many additional pharmacological properties. Thus, it has been experimentally proven, in vivo and in vitro that it is effective to treat certain allergies, anemia, cancer, hepatotoxicity, viral and cardiovascular diseases, hyperglycemia, hyperlipidemia, immunodeficiency, and inflammatory processes, among others. Several of these activities are attributed to Spirulina itself or to some of its components including fatty acids omega-3 or omega-6, beta-carotene, alpha-tocopherol, phycocyanin, phenol compounds, and a recently isolated complex, Ca-Spirulan (Ca-SP). This paper aims to update and critically review the results published over the last few years with regards to these properties. The conclusion is that even if this cyanobacterium has been one of the most extensively studied from the chemical, pharmacological and toxicological points of view, it is still necessary to expand the research in order to have more consistent data for its possible use in human beings.

Reproductive toxicity of gamma-ethyl-gamma-phenyl-butyrolactone, a new anticonvulsant and hypnotic drug, in mice. Fertility and peri- and post-natal studies.

The reproductive toxicity of gamma-ethyl-gamma-phenyl-butyrolactone (EPBL, CAS 53380-21-5), a new anticonvulsant and hypnotic drug, was investigated by performing fertility and peri- and post-natal studies in mice. In both studies, EPBL was administered by gavage at 0, 50, 10, or 200 mg/kg doses. The first study found parent toxicity as measured by reduced body weight at the higher dose. At the same dose, the number of live fetuses was decreased. However, neither male or female fertility nor the reproductive performance of mice were affected. The results of the second study showed that the only negative effects were a depression of maternal weight gain and a decrease in body weight of the litter at birth which was 200 mg/kg. A reduction in the survival rate was also seen. There was no evidence that treatment of F0 females from day 15 of pregnancy to day 21 post-partum affected either the reproductive capacity of the F1 offspring or the development of F2 progenies. The non observed effects levels (NOEL) for both studies can be estimated at 100 mg/kg.

Farmacología y toxicología del alga Spirulina / Pharmacology and toxicology of the alga spirulina

La Spirulina, alga azul-verde filamentosa unicelular, ha sido consumida desde tiempos remotos en México y Africa Central, en donde crece de manera seminatural o natural. Actualmente se cultiva en algunos países por metódos sintéticos. Hasta recientemente el interés en esta alga se centraba en su valor nutritivo que mostró ser casi igual al de proteínas de otras plantas. Sin embargo, algunos estudios preclínicos sugieren que también poseen propiedades terapéuticas interesantes, tales como hipocolesterolemiante, inmunológica, antiviral y antimutagénica. Esto ha llevado a evaluaciones toxicológicas detalladas. El contenido de ácidos nucleicos y la presencia de metales, de aminas biogéncias y de compuestos químicos orgánicos, han sido negativos o están bajo de las concentraciones tolerables recomendadas por agencias internacionales de regulación de alimentos. Los experimentos en animales de toxicidad aguda, subcrónica, crónica, de reproducción, mutagenicidad y teratogenicidad, no han revelado ningún efecto adverso al alga, en todos los casos, la cantidad de Spirolina administradas a los animales fueron iguales o superiores al consumo humano. Sin embargo, hay pocos estudios de los efectos de consumo de Spirulina en humanos. Esta área necesita más estudios

Evaluación de la toxicidad del indorrenato sobre la reproducción / The toxicity evaluation of indorenate on the reproductive system

Se estudiaron los efectos del indorrenato, un nuevo fármaco antihipertensivo, sobre la fertilidad, desarrollo peri-postnatal y embrionario en rata, a dosis de 0, 10, 20, 40 y 60 mg/kg/día, administrados oralmente. Durante el estudio de fertilidad, con excepción de la dosis de 60 mg/kg, ningún tratamiento afectó el peso de los progenitores, la fertilidad, el peso fetal o la sobrevivencia. Tampoco las dosis bajas dieron lugar a retardo en aparición del reflejo de enderezamiento, despliegue de pabellón auricular y respuesta al ruido. Las dosis de 40 y 60 mg/kg, por su parte, disminuyeron significativamente el número de fetos vivos y aumentó el de reabsorciones embrionarias. En el estudio peri-postnatal, 40 y 60 mg/kg aumentaron el número de fetos muertos al nacer, y la segunda, afectó también su sobrevivencia, el aumento ponderal y el reflejo de caída. La capacidad reproductiva de la generación F1 no fue modificada. El fármaco no provocó embriotoxicidad ni teratogenicidad, administrado durante el período de organogénesis, en contraste con la serotonina, de la cual es análogo estructural. Se concluye que el indorrenato hasta la dosis de 20 mg/kg, que representa aproximadamente 1200 veces la que se pretende utilizar en pacientes hipertensos, no ejerce efecto toxico aparente sobre la reproducción, desarrollo embrionario y fetal en rata