Treatments for diabetes mellitus type II: New perspectives regarding the possible role of calcium and cAMP interaction.

Diabetes mellitus (DM) is among the top ten causes of death worldwide. It is considered to be one of the major global epidemics of the 21st century, with a significant impact on public health budgets. DM is a metabolic disorder with multiple etiologies. Its pathophysiology is marked by dysfunction of pancreatic ß-cells which compromises the synthesis and secretion of insulin along with resistance to insulin action in peripheral tissues (muscle and adipose). Subjects presenting insulin resistance in DM type 2 often also exhibit increased insulin secretion and hyperinsulinemia. Insulin secretion is controlled by several factors such as nutrients, hormones, and neural factors. Exocytosis of insulin granules has, as its main stimulus, increased intracellular calcium ([Ca+2]i) and it is further amplified by cyclic AMP (cAMP). In the event of this hyperfunction, it is very common for ß-cells to go into exhaustion leading to failure or death. Several animal studies have demonstrated pleiotropic effects of L-type Ca2+ channel blockers (CCBs). In animal models of obesity and diabetes, treatment with CCBs promoted restoration of insulin secretion, glycemic control, and reduction of pancreatic ß-cell apoptosis. In addition, hypertensive individuals treated with CCBs presented a lower incidence of DM when compared with other antihypertensive agents. In this review, we propose that pharmacological manipulation of the Ca2+/cAMP interaction system could lead to important targets for pharmacological improvement of insulin secretion in DM type 2.

Physical exercise alters the activation of downstream proteins related to BDNF-TrkB signaling in male Wistar rats with epilepsy.

There are a considerable number of studies concerning the behavioral effects of physical exercise on the epileptic brain; however, the intracellular signaling mechanisms involved remain unclear. We investigated the effects of aerobic exercise on hippocampal levels of brain-derived neurotrophic factor (BDNF), expression of its receptor tropomyosin receptor kinase B (TrkB), and activation of intracellular proteins related to BDNF-TrkB signaling in male Wistar rats with pilocarpine-induced epilepsy. Thirty days after the first spontaneous seizure, rats from the exercise group undertook a 30-day physical exercise program on the treadmill. Thereafter, BDNF levels, expression of TrkB, and activation of intracellular proteins were quantified by enzyme-linked immunosorbent assay, Western blotting, and multiplex assay, respectively. Statistical analyses were conducted using nonparametric tests. Rats with epilepsy presented decreased BDNF levels compared with control rats. BDNF levels increased significantly in the exercise group compared with the epileptic and control groups. Expression of full-length and truncated TrkB was increased in rats with epilepsy, and physical exercise restored its expression to control levels. RAC-alpha serine/threonine-protein kinase, mammalian target of rapamycin, and extracellular signal-regulated kinase activation were reduced in rats with epilepsy, and exercise increased activation compared with control and epilepsy groups. Increased cAMP response element binding protein activation was observed in the exercise group compared with the epilepsy group. Our findings indicate that the beneficial effects of exercise in the epileptic brain can be in part related to alterations in the activation of proteins related to the BDNF-TrkB signaling pathway.

Resistance Exercise Reduces Seizure Occurrence, Attenuates Memory Deficits and Restores BDNF Signaling in Rats with Chronic Epilepsy.

Epilepsy is a disease characterized by recurrent, unprovoked seizures. Cognitive impairment is an important comorbidity of chronic epilepsy. Human and animal model studies of epilepsy have shown that aerobic exercise induces beneficial structural and functional changes and reduces the number of seizures. However, little is yet understood about the effects of resistance exercise on epilepsy. We evaluated the effects of a resistance exercise program on the number of seizures, long-term memory and expression/activation of signaling proteins in rats with epilepsy. The number of seizures was quantified by video-monitoring and long-term memory was assessed by an inhibitory avoidance test. Using western blotting, multiplex and enzyme-linked immunosorbent assays, we determined the effects of a 4-week resistance exercise program on IGF-1 and BDNF levels and ERK, CREB, mTOR activation in the hippocampus of rats with epilepsy. Rats with epilepsy submitted to resistance exercise showed a decrease in the number of seizures compared to non-exercised epileptic rats. Memory deficits were attenuated by resistance exercise. Rats with epilepsy showed an increase in IGF-1 levels which were restored to control levels by resistance exercise. BDNF levels and ERK and mTOR activation were decreased in rats with epilepsy and resistance exercise restored these to control levels. In conclusion, resistance exercise reduced seizure occurrence and mitigated memory deficits in rats with epilepsy. These resistance exercise-induced beneficial effects can be related to changes in IGF-1 and BDNF levels and its signaling protein activation. Our findings indicate that the resistance exercise might be included as complementary therapeutic strategy for epilepsy treatment.

Epilepsy and exercise: An experimental study in female rats.

OBJECTIVE: Epilepsy is the most common neurological chronic condition worldwide, affecting about 2% of world population. Temporal lobe epilepsy (TLE) reaches 40% of all cases of this condition, and it is highly refractory to pharmacological treatment. Physical activity has been suggested as complementary therapy for epilepsy. However, there is no consistent information whether all these effects are plenty applicable to females, since clinical and experimental studies concerning physical exercise and epilepsy are largely performed in males. Females are worthy of special attention due to gender specific particularities such as hormonal cyclical rhythm and possible pregnancy. Therefore, this study aimed to investigate the impact of two types of exercise programs (Forced and Voluntary) in female Wistar rats submitted to temporal lobe epilepsy induced by pilocarpine. METHODS: Animals were divided into four groups: Control (healthy), Epilepsy, Epilepsy/Forced (exercise in a treadmill) and Epilepsy/Voluntary (free access to wheel). Behavioral and histological analyses were evaluated among groups. RESULTS: Voluntary exercise was able to reduce seizure frequency and anovulatory estrous cycle occurrence. Yet, both types of exercise attenuated the mossy fiber sprouting in dentate gyrus. CONCLUSION: Our results indicate that voluntary exercise exerts a positive effect on epilepsy in female gender. Further investigations are necessary to better elucidate mechanisms involved in these responses, since these effects do not act in the same manner in male and female rats.

Effects of different physical exercise programs on susceptibility to pilocarpine-induced seizures in female rats.

In epilepsy, the most common serious neurological disorder worldwide, several investigations in both humans and animals have shown the effectiveness of physical exercise programs as a complementary therapy. Among the benefits demonstrated, regular exercise can decrease the number of seizures as well as improve cardiovascular and psychological health in people with epilepsy. While many studies in animals have been performed to show the beneficial effects of exercise, they exclusively used male animals. However, females are also worthy of investigation because of their cyclical hormonal fluctuations and possible pregnancy. Considering the few animal studies concerning seizure susceptibility and exercise programs in females, this study aimed to verify whether exercise programs can interfere with seizure susceptibility induced by pilocarpine in adult female Wistar rats. Animals were randomly divided into three groups: control, forced, and voluntary (animals kept in a cage with a wheel). After the final exercise session, animals received a pilocarpine hydrochloride (350 mg/kg i.p.; Sigma) injection to induce seizures. To measure the intensity of pilocarpine-induced motor signs, we used a scale similar to that developed by Racine (1972) in the kindling model. During a 4-h period of observation, we recorded latency for first motor signs, latency for reaching SE, number of animals that developed SE, and intensity of pilocarpine-induced motor signs. No difference was observed among groups in latency for first motor signs and in the number of animals that developed SE. Although the voluntary group presented more intense motor signs, an increased latency for developing SE was observed compared with that in forced and control groups. Our behavioral results are not enough to explain physiological and molecular pathways, but there are mechanisms described in literature which may allow us to propose possible explanations. Voluntary exercise increased latency to SE development. Further investigation is necessary to elucidate the pathways involved in these results, while more studies should be performed regarding gender specific differences.

Relationship between seizure frequency and number of neuronal and non-neuronal cells in the hippocampus throughout the life of rats with epilepsy.

The relationship between seizure frequency and cell death has been a subject of controversy. To tackle this issue, we determined the frequency of seizures and the total number of hippocampal cells throughout the life of rats with epilepsy using the pilocarpine model. Seizure frequency varied in animals with epilepsy according to which period of life they were in, with a progressive increase in the number of seizures until 180 days (sixth months) of epileptic life followed by a decrease (330 days-eleventh month) and subsequently stabilization of seizures. Cell counts by means of isotropic fractionation showed a reduction in the number of hippocampal neuronal cells following 30, 90, 180 and 360 days of spontaneous recurrent seizures (SRS) in rats compared to their controls (about 25%-30% of neuronal cell reduction). In addition, animals with 360 days of SRS showed a reduction in the number of neuronal cells when compared with animals with 90 and 180 days of seizures. The total number of hippocampal non-neuronal cells was reduced in rats with epilepsy after 30 days of SRS, but no significant alteration was observed on the 90th, 180th and 360th days. The total number of neuronal cells was negatively correlated with seizure frequency, indicating an association between occurrence of epileptic seizures throughout life and neuronal loss. In sum, our results add novel data to the literature concerning the time-course of SRS and hippocampal cell number throughout epileptic life.

The beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling is impaired by anabolic androgenic steroids.

Previous studies have shown that strength exercise improves memory and increases expression of a myriad of proteins involved on neuronal survival and synaptic plasticity in the hippocampus. Conversely, chronic exposure to supraphysiological levels of anabolic androgenic steroids (AAS) can induce psychiatric abnormalities, cognitive deficits, impair neurotransmission, alter the levels of neurotrophic factors, decrease cell proliferation and neurogenesis, and enhance neuronal cell death. In the present study, we investigated the effects of the AAS nandrolone decanoate (ND) administration during a strength exercise program on cell proliferation, apoptotic status and brain-derived neurotrophic factor (BDNF) expression in the rat hippocampus. Adult male Wistar rats were subjected to 4 weeks of progressive strength exercise in a vertical ladder apparatus with or without daily doses (5.0 mg/kg, SC) of ND. Immunohistochemistry analysis revealed that strength exercise increased significantly the number of Ki-67-positive cells (a cell proliferation marker) in dentate gyrus (DG) of hippocampus. However, this effect was abrogated when strength exercise was combined with ND. Although western blot analysis of whole hippocampus showed no significant differences in Bax and Bcl-2 protein expression among groups, the immunoreactivity of the pro-apoptotic protein Bax was significantly increased in DG, CA1 and CA3 hippocampal subfields of sedentary rats treated with ND. Moreover, the increase in the immunoreactivity of anti-apoptotic protein Bcl-2 (DG and CA3) induced by strength exercise was diminished by ND. There were no significant differences in BDNF expression among experimental groups. Therefore, the present findings suggest that the beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling are impaired by ND.