A new class of peptides from wasp venom: a pathway to antiepileptic/neuroprotective drugs.

The ability of venom-derived peptides to disrupt physiological processes in mammals provides an exciting source for pharmacological development. Our research group has identified a new class of neuroactive peptides from the venom of a Brazilian social wasp, Polybia occidentalis, with the potential pharmacological profile to treat epilepsies. The study was divided into five phases: Phase 1 concerned the extraction, isolation and purification of Occidentalin-1202(n) from the crude venom, followed by the synthesis of an identical analogue peptide, named Occidentalin-1202(s). In Phase 2, we described the effects of both peptides in two acute models of epilepsy-kainic acid and pentylenetetrazole-induced model of seizures-and measured estimated ED50 and therapeutic index values, electroencephalographic studies and C-fos evaluation. Phase 3 was a compilation of advanced tests performed with Occidentalin-1202(s) only, reporting histopathological features and its performance in the pilocarpine-induced status epilepticus. After the determination of the antiepileptic activity of Occidentalin-1202(s), Phase 4 consisted of evaluating its potential adverse effects, after chronic administration, on motor coordination (Rotarod) and cognitive impairment (Morris water maze) tests. Finally, in Phase 5, we proposed a mechanism of action using computational models with kainate receptors. The new peptide was able to cross the blood-brain barrier and showed potent antiseizure effects in acute (kainic acid and pentylenetetrazole) and chronic (temporal lobe epilepsy model induced by pilocarpine) models. Motor and cognitive behaviour were not adversely affected, and a potential neuroprotective effect was observed. Occidentalin-1202 can be a potent blocker of the kainate receptor, as assessed by computational analysis, preventing glutamate and kainic acid from binding to the receptor's active site. Occidentalin-1202 is a peptide with promising applicability to treat epilepsy and can be considered an interesting drug model for the development of new medicines.

Ischemia-induced retinal injury is attenuated by Neurovespina, a peptide from the venom of the social wasp Polybia occidentalis.

Neurovespina is a synthetic peptide modified from Occidentalin-1202, a nine amino acid residue peptide isolated from the venom of the social wasp Polybia occidentalis. Previous studies showed that this peptide has a neuroprotective effect on the central nervous system, but its action on the eye has not been explored. So, the objective of this work was to investigate the neuroprotective effect of Neurovespina on the retina and its angiogenic potential in the chicken chorioallantoic membrane (CAM). Retinal ischemia was induced in rats by acute elevation of intraocular pressure (IOP). Electroretinography (ERG) measurements, histopathological and immunohistochemical analysis, and transmission electronic microscopy (TEM) records were performed to check the neuroprotection effect of Neurovespina in the retina of the animals. The angiogenic activity of the peptide was investigated by CAM assay. The results showed that Neurovespina was able to reduce the effects induced by ischemic injury, preventing the reduction of a- and b-waves in the scotopic ERG. Histopathological and immunohistochemistry assays showed that Neurovespina, mainly at 60 µg/ml, protected all layers of the retina. The CAM assay revealed that the peptide promoted the reduction of CAM vessels. So, Neurovespina was able to protect retinal cells from ischemic insult and has an antiangiogenic effect, which can be considered as a promising neuroprotective agent for intravitreal application.

Ceftriaxone pretreatment confers neuroprotection in rats with acute glaucoma and reduces the score of seizures induced by pentylenotetrazole in mice.

ß-Lactam antibiotics such as ceftriaxone, are potent stimulators of the expression of l-glutamate transporter GLT-1 and may exert neuroprotective effects when chronically used in rats and mice. In this study, we used two animal models to test the neurological effect of subchronic treatment with ceftriaxone: experimental acute glaucoma in Wistar rats and induction of acute seizures with pentylenetetrazole in mice. We also assessed the performance of mice in the rotarod to calculate therapeutic indexes and exploratory activity in the open field. Our results showed that subchronic use of ceftriaxone was neuroprotective in both models, reducing injury in acute ischemia and ischemia/reperfusion in specific layers of retina and leading to a decrease in the seizure severity score. In behavioral experiments, we observed that ceftriaxone increased hyperactivity followed by a decrease in exploratory behavior in the open field, and there was no motor impairment in the rotarod test. We conclude that ceftriaxone may be useful as a tool in the development of new neuroprotective drugs targeting diseases which present a possible dysfunction in the balance of glutamatergic neurotransmission.

Marine Depsipeptides as Promising Pharmacotherapeutic Agents.

Depsipeptides are a group of biologically active peptides that have at least one of the amide bonds replaced by an ester bond. These peptides sometimes present additional chemical modifications, including unusual amino acid residues in their structures. Depsipeptides are known to exhibit a large array of bioactivities, such as anticancer, antiproliferative, antimicrobial, antiviral and antiplasmodial properties. They are commonly found in marine organisms: bacteria, tunicates, mollusks, sponges, and others. Herein, we summarize the latest insights about marine depsipeptides, their mechanisms of action and potential as therapeutic agents.

Anxiolytic activity and evaluation of potentially adverse effects of a bradykinin-related peptide isolated from a social wasp venom.

Anxiety disorders are major health problems in terms of costs stemming from sick leave, disabilities, healthcare and premature mortality. Despite the availability of classic anxiolytics, some anxiety disorders are still resistant to treatment, with higher rates of adverse effects. In this respect, several toxins isolated from arthropod venoms are useful in identifying new compounds to treat neurological disorders, particularly pathological anxiety. Thus, the aims of this study were to identify and characterize an anxiolytic peptide isolated from the venom of the social wasp Polybia paulista. The peptide was identified as Polisteskinin R, with nominal molecular mass [M+H](+)=1301Da and primary structure consisting of Ala-Arg-Arg-Pro-Pro-Gly-Phe-Thr-Pro-Phe-Arg-OH. The anxiolytic effect was tested using the elevated plus maze test. Moreover, adverse effects on the spontaneous behavior and motor coordination of animals were assessed using the open field and rotarod tests. Polisteskinin R induced a dose-dependent anxiolytic effect. Animals treated with the peptide and diazepam spent significantly more time into the open arms when compared to the groups treated with the vehicle and pentylenetetrazole. No significant differences in spontaneous behavior or motor coordination were observed between the groups, showing that the peptide was well tolerated. The interaction by agonists in both known BK receptors induces a variability of physiological effects; Polisteskinin R can act on these receptors, inducing modulatory activity and thus, attenuating anxiety behaviors. The results of this study demonstrated that the compound Polisteskinin R exerted potent anxiolytic effects and its analogues are promising candidates for experimental pharmacology.

Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools.

Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for the control of neurodegenerative diseases. These venoms and their components are well-known and irrefutable sources of neuroprotectors or neuromodulators. In this respect, the present study reviews our current understanding of the mechanisms of action and future prospects regarding the use of new drugs derived from wasp and bee venom in the treatment of major neurodegenerative disorders, including Alzheimer's Disease, Parkinson's Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

Neuroactive compounds obtained from arthropod venoms as new therapeutic platforms for the treatment of neurological disorders.

The impact of neurological disorders in society is growing with alarming estimations for an incidence increase in the next decades. These disorders are generally chronic and can affect individuals early during productive life, imposing real limitations on the performance of their social roles. Patients can have their independence, autonomy, freedom, self-image, and self-confidence affected. In spite of their availability, drugs for the treatment of these disorders are commonly associated with side effects, which can vary in frequency and severity. Currently, no effective cure is known. Nowadays, the biopharmaceutical research community widely recognizes arthropod venoms as a rich source of bioactive compounds, providing a plethora of possibilities for the discovery of new neuroactive compounds, opening up novel and attractive opportunities in this field. Several identified molecules with a neuropharmacological profile can act in the central nervous system on different neuronal targets, rendering them useful tools for the study of neurological disorders. In this context, this review aims to describe the current main compounds extracted from arthropod venoms for the treatment of five major existing neurological disorders: stroke, Alzheimer's disease, epilepsy, Parkinson's disease, and pathological anxiety.

Pharmacological characterization of Synoeca cyanea venom: an aggressive social wasp widely distributed in the Neotropical region.

The venom of social wasps has been poorly studied so far, despite the high number of accidents in humans and assessment of the use of these wasps as a biological control of pests. The study of the pharmacological effects of the venom is of great importance since the poisoning is dangerous causing serious systemic effects, including death in the case of multiple attacks. In this study, the pharmacological activities of venom from the social wasp Synoeca cyanea were evaluated by the following assays: LD50 in mice, the behavioural effects and the hemorrhagic activity induced by the venom in mice, the oedematogenic activity in rat, the haemolysis in human blood, the stimulating effect on guinea-pig smooth muscle, and the antimicrobial activity. The aim was to determine the toxic effects of venom and to perform a comparative study with earlier work conducted with venom from other wasp species. Results showed that S. cyanea venom produced a potent dose-dependent oedema, as well as antibacterial and haemolytic activities, suggesting the presence of histamine, serotonin, kinins and other molecules related to increased vascular permeability and cytolytic activity in this venom. Despite previous studies with wasp venoms, S. cyanea venom presented a slight hemorrhagic effect. Data obtained in the smooth muscle assay also suggest the presence of BK or analogues in S. cyanea whole venom. The knowledge of symptoms and effects produced by S. cyanea venom is critical for health organizations, in order to improve clinical treatment in accidents caused by wasp stings.

Anticonvulsant and anxiolytic activity of the peptide fraction isolated from the venom of the social wasp Polybia paulista.

BACKGROUND: Arthropod venoms have attracted interest because they represent a source of neuroactive compounds that can be useful tools in neuroscience and pharmacological investigations. OBJECTIVE: The purpose of the present work was to evaluate the anticonvulsant, anxiolytic, and behavioral effects of the peptide fraction separated from venom of the social wasp. MATERIALS AND METHODS: The low- molecular-weight compounds of the venom were separated by ultrafiltration and the bioassays were performed to test anticonvulsant and anxiolytic effects, as well as alterations in the spontaneous behavior of the animals. RESULTS: Intracerebroventricular injections of the compounds induced dose-dependent anticonvulsant effects and a potent anxiolytic activity. Regarding behavioral effects, no significant differences were observed in relation to the saline control group. CONCLUSION: The low-molecular-weight compounds of the venom of Polybia paulista include neuroactive peptides that can be used as pharmacological resources for anticonvulsant and anxiolytic drug research.