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News Article | March 2, 2017

Researchers from the University of Iowa Carver College of Medicine and the University of Miami Miller School of Medicine have shown that a neuroprotective compound tested in rats provides two-pronged protection for brain cells during stroke and improves physical and cognitive outcomes in the treated animals. Every year, nearly 800,000 Americans have a stroke and almost 130,000 die. Survivors often are left with long-term physical and cognitive disability that significantly alters their lives. When a stroke interrupts the brain's blood supply, mature brain cells (neurons) die. In addition, reestablishing blood flow, known as reperfusion, also leads to processes that cause cell death. A part of the brain's natural response to stroke injury is to increase production of new brain cells in two specific regions (the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricles), which normally make a smaller number of new brain cells every day. Unfortunately, the vast majority of these newborn cells die within one to two weeks, limiting the benefit of this potential repair process. Minimizing the loss of brain cells is a primary goal for new stroke therapies. "If we could prevent the mature brain cells from dying that would be beneficial," says Andrew Pieper, MD, PhD, professor of psychiatry in the UI Carver College of Medicine and co-senior study author. "But if we could also support or enhance this surge in neurogenesis (birth of new neurons), we might be able to further foster recovery, especially in terms of cognitive function, which is critically dependent on the hippocampus." Using rats, Pieper and his colleagues Zachary B. Loris and W. Dalton Dietrich, PhD, tested the effects of a compound called P7C3-A20 on these two aspects of neuroprotection following ischemic stroke. Blood flow to the rats' brains was interrupted for 90 minutes and then the blockage was cleared allowing reperfusion. One group of rats was given the P7C3-A20 compound twice daily for seven days following the stroke. P7C3-A20 has previously been shown to prevent brain cell death in other animal models of neurologic injury, including Parkinson's disease, amyotrophic lateral sclerosis, stress-associated depression, and traumatic brain injury. In terms of the brain itself, the P7C3-A20 compound reduced loss of brain tissue (atrophy) and increased survival of newborn neurons six weeks after stroke. In addition to the improved survival of both mature and newborn neurons, rats that received the P7C3-A20 compound for seven days after stroke also had better physical and cognitive outcomes than untreated rats. Treated rats had improved balance and coordination one week after stroke, and improved learning and memory one month after stroke. The findings were published recently in the journal Experimental Neurology. "There is no previous demonstration of a pharmacologic agent that both protects mature neurons from dying and also boosts the net magnitude of neurogenesis," Pieper says. "Our compound is beneficial in this animal model of stroke, and we're hopeful that it might eventually benefit patients." "Currently there are limited treatments for acute stroke that make a real difference in patient's lives. There is an urgent need to identify, test, and translate new therapies to the clinic," adds Dietrich, co-senior study author and Scientific Director of The Miami Project to Cure Paralysis, professor of neurological surgery, neurology, biomedical engineering and cell biology at the University of Miami where the studies were conducted. "The ability to both protect and repair the injured nervous system has major implications on how we think about improving outcomes in millions of people each year with acute neurological injuries." The neuronal protection provided by the P7C3-A20 compound was also associated with a boost in the levels of a substance called nicotinamide adenine dinucleotide (NAD) in the rats' brains. NAD is emerging as an important player in neuronal health and survival. Levels of this substance are depleted during stroke, and it has been proposed that increasing NAD levels may be a therapeutic target for treating stroke. In this study, P7C3-A20 treatment restored NAD to normal levels in the rats' cortex after a stroke. Importantly, the study examined the effects of P7C3-A20 on cognitive and physical outcomes well beyond the time of the initial stroke. The sustained physical and cognitive improvement seen in the rats up to one month after the stroke suggests that the P7C3-A20 compound provides a long-term benefit. "We found we can give the compound in this critical period immediately after the stroke and it has a lasting effect," notes Pieper, who also is a professor of neurology, radiation oncology, and a psychiatrist with the Iowa City Veterans Affairs Health Care System. In recent years, advances in treatments that break up or remove stroke-causing blood clots have reduced the death rate for stroke and are improving outcomes for patients. The researchers hope that a treatment based on P7C3-A20 used in addition to the clot-clearing therapies might further improve outcomes by protecting brain cells during the traumatic ischemia/reperfusion period. The research was supported by funding from the American Heart Association, The Miami Project to Cure Paralysis, the Mary Alice Smith Fund for Neuropsychiatry Research, the Titan Neurologic Research fund, and the University of Iowa and the Department of Veterans Affairs.

News Article | February 6, 2017

Scientists at the Medical Research Council Brain Network Dynamics Unit at the University of Oxford have pinpointed two distinct mechanisms in the human brain that control the balance between speed and accuracy when making decisions. Their discovery, published in eLife, sheds new light on the networks that determine how quickly we choose an option, and how much information we need to make that choice. A more detailed understanding of this intricate wiring in the brain holds the key to developing better treatments for neurological disorders such as Parkinson's disease. The fundamental trade-off between speed and accuracy in decision making has been studied for more than a century, with a number of studies suggesting that the subthalamic nucleus region of the brain plays a key role. "Previous behavioural studies of decision making do not tell us about the actual events or networks that are responsible for making speed-accuracy adjustments," says senior author Peter Brown, Professor of Experimental Neurology at the University of Oxford. "We wanted to address this by measuring the exact location and timing of electrical activity in the subthalamic nucleus and comparing the results with behavioural data collected while a decision-making task is being performed." Brown and his team first studied the reaction times of 11 patients with Parkinson's disease and 18 healthy participants, who were each asked to perform a moving-dots task. This required them to decide whether a cloud of moving dots appeared to be moving to the left or the right. The difficulty of the task was varied by changing the number of dots moving in one direction, and the participants were given randomly alternating instructions to perform the task with either speed or accuracy. The researchers found that participants made much faster decisions when the task was easier - with the dots moving in a single direction - and when instructed to make a quick decision. They also found, in line with previous studies, that participants made significantly more errors during tests where they spent longer making a decision after being instructed to emphasise accuracy. Using a computational model, they saw that it took longer in the more difficult tests for the brain to accumulate the necessary information to reach a critical threshold and make a decision. When the participants were asked to focus on speed, this threshold was significantly lower than when they focused on accuracy. "The next step was to determine the activated networks in the brain that control these behavioural modifications and the trade-off between fast and accurate decisions," explains first author and postdoctoral fellow Damian Herz. "We measured the electrical activity of groups of nerve cells within the subthalamic nucleus in patients with Parkinson's disease, who had recently been treated with deep brain stimulation. We found two distinct neural networks that differ in the way they are ordered and the way they respond to tasks. "One network increases the amount of information required before executing a decision and is therefore more likely to be activated when accuracy is important, while the second network tends to lower this threshold, especially when the choice needs to be made quickly." The findings add to the increasing evidence that the pre-frontal cortex region of the brain contributes to decision making and opens up further interesting avenues to explore. "We know that changes in activity of one of the sites we identified is also related to movement control," adds Brown. "Close relationships between these neural networks could mean that a common signal is responsible for adjustments in both the speed of decision and of the resulting movement. A better understanding of these mechanisms might make it possible to focus therapeutic interventions on specific neural circuits to improve treatment of neurological disorders in the future."

Goto E.M.,Federal University of São Paulo | Silva M.d.P.,Nove de Julho University | Perosa S.R.,Experimental Neurology | Arganaraz G.A.,Experimental Neurology | And 5 more authors.
Neuropeptides | Year: 2010

The aim of this study was to analyze the expression of survival-related molecules such Akt and integrin-linked kinase (ILK) to evaluate Akt pathway activation in epileptogenesis process. Furthermore, was also investigated the mRNA expression of neuropeptide Y, a considered antiepileptic neuropeptide, in the pilocarpine-induced epilepsy. Male Wistar rats were submitted to the pilocarpine model of epilepsy. Hippocampi were removed 6 h (acute phase), 12 h (late acute), 5d (silent) and 60d (chronic) after status epilepticus (SE) onset, and from animals that received pilocarpine but did not develop SE (partial group). Hippocampi collected were used to specify mRNA expression using Real-Time PCR. Immunohistochemistry assay was employed to place ILK distribution in the hippocampus and Western blot technique was used to determine Akt activation level. A decrease in ILK mRNA content was found during acute (0.39 ± 0.03) and chronic (0.48 ± 0.06) periods when compared to control group (0.87 ± 0.10). Protein levels of ILK were also diminished during both periods. Partial group showed increased ILK mRNA expression (0.80 ± 0.06) when compared with animals in the acute stage. Silent group had ILK mRNA and immunoreactivity similar to control group. Western blot assay showed an augmentation in Akt activation in silent period (0.52 ± 0.03) in comparison with control group (0.44 ± 0.01). Neuropeptide Y mRNA expression increased in the partial group (1.67 ± 0.22) and in the silent phase (1.45 ± 0.29) when compared to control group (0.36 ± 0.12). Results suggest that neuropeptide Y (as anticonvulsant) might act in protective mechanisms occurred during epileptic phenomena. Together with ILK expression and Akt activation, these molecules could be involved in hippocampal neuroprotection in epilepsy. © 2009 Elsevier Ltd. All rights reserved.

Longone P.,Molecular Neurobiology Unit | di Michele F.,Experimental Neurology | D'Agati E.,University of Rome Tor Vergata | Romeo E.,University of Rome Tor Vergata | And 2 more authors.
Frontiers in Endocrinology | Year: 2011

Anxiety disorders are the most common psychiatric disorders. They are frequently treated with benzodiazepines, which are fast acting highly effective anxiolytic agents. However, their long-term use is impaired by tolerance development and abuse liability. In contrast, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are considered as first-line treatment but have a slow onset of action. Neurosteroids are powerful allosteric modulators of GABAA and glutamate receptors. However, they also modulate sigma recep-tors and they are modulated themselves by SSRIs. Both pre-clinical and clinical studies have shown that neurosteroid homeostasis is altered in depression and anxiety disorders and antidepressants may act in part through restoring neurosteroid disbalance. Moreover, novel drugs interfering with neurosteroidogenesis such as ligands of the translocator pro-tein (18 kDa) may represent an attractive pharmacological option for novel anxiolytics which lack the unwarranted side effects of benzodiazepines. Thus, neurosteroids are important endogenous neuromodulators for the physiology and pathophysiology of anxiety and they may constitute a novel therapeutic approach in the treatment of these disorders. © 2011 Longone, di Michele, D'Agati, Romeo, Pasini and Rupprecht.

Jardim A.P.,Federal University of São Paulo | Neves R.S.C.,Federal University of São Paulo | Caboclo L.O.S.F.,Federal University of São Paulo | Lancellotti C.L.P.,Santa Casa de Sao Paulo | And 5 more authors.
Arquivos de Neuro-Psiquiatria | Year: 2012

Objective: To analyze retrospectively a series of patients with temporal lobe epilepsy (TLE) and mesial temporal sclerosis (MTS), and the association of patterns of hippocampal sclerosis with clinical data and surgical prognosis. Method: Sixty-six patients with medically refractory TLE with unilateral MTS after anterior temporal lobectomy were included. Quantitative neuropathological evaluation was performed on NeuN-stained hippocampal sections. Patient's clinical data and surgical outcome were reviewed. Results: Occurrence of initial precipitating insult (IPI), as well as better postoperative seizure control (i.e. Engel class 1), were associated with classical and severe patterns of hippocampal sclerosis (MTS type 1a and 1b, respectively). Conclusion: Quantitative evaluation of hippocampal neuronal loss patterns predicts surgical outcome in patients with TLE-MTS. Key words epilepsy, temporal lobe, mesial temporal sclerosis, hippocampal sclerosis, pathology, surgical prognosis with TLE-MTS.

Traumatic brain injury (TBI) affects more than half a million infants and children in the United States every year. New research shows that specific antibiotics used to inhibit the brain's inflammatory response can help adults, while at the same time negatively affecting children and infants. There are no drugs available to treat TBI, but there are medical treatments used to improve the outcome in people who had suffered serious head injuries. The treatment was found to have a negative effect on the brains which did not complete the development process. The study, published in the journal Experimental Neurology, was conducted by researchers at Drexel University College of Medicine. It showed that when antibiotics were administered to newborn rats in the immediate aftermath of the injury, it aggravated the cognitive impairment. "The developing brain is not the same as the fully mature brain. This study suggests that acute interventions targeting the inflammatory cascade may not be a viable strategy for treating traumatic brain injury in infants and young children," noted Ramesh Raghupathi, PhD, a professor of neurobiology and anatomy in the College of Medicine. What the minocycline drug does is decrease the activation of microglia, the primary immune cells located in the spinal cord and the brain, responsible with protecting the body against foreign pathogens. However, this inhibition of microglia only seems to work in adult brains, while the pediatric model shows a different response, "There was a lot of cell death, damage and inflammation," noted Raghupathi said, lead author of the study. The team tested the drug, treating the newborn rats with minocycline, in one daily dosage over a three-day period. The results showed no improvement in the brain activity. Further, the researchers extended the period to nine days instead of just three, and the baby rats showed significant memory issues as well as complementary behavioral problems. The researchers attributed this result to the role microglia plays in brain development, cleaning the brain of debris and dead neurons as to make room for the functional neurons left to work under normal conditions. By inhibiting this function inside the brains of newborns, the normal process of brain maturation is negatively affected, and cognitive functions can suffer long-term impairment. "Whereas injury-induced spatial learning deficits remained unaffected by minocycline treatment, memory deficits appeared to be significantly worse. Sex had minimal effects on either injury-induced alterations or the efficacy of minocycline treatment. Collectively, these data demonstrate the differential effects of minocycline in the immature brain following impact trauma and suggest that minocycline may not be an effective therapeutic strategy for TBI in the immature brain," noted the research. In the following researches, the scientists will administer the treatment after three or four weeks, as opposed to the 11-days old rats used in the current research, to evaluate the effects. More time for the brain development process could make the difference between a positive and a negative outcome of the treatment, according to the researchers, who wish to establish the age from when on the treatment doesn't cause further cognitive and behavioral impairment, with as much precision as possible. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.

Di Michele F.,Experimental Neurology | Luchetti S.,Royal Netherlands Academy of Arts and science | Bernardi G.,Experimental Neurology | Bernardi G.,University of Rome Tor Vergata | And 2 more authors.
Frontiers in Neuroendocrinology | Year: 2013

Parkinson's disease (PD) is associated with a massive loss of dopaminergic cells in the substantia nigra leading to dopamine hypofunction and alteration of the basal ganglia circuitry. These neurons, are under the control, among others, of the excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA) systems. An imbalance between these systems may contribute to excitotoxicity and dopaminergic cell death. Neurosteroids, a group of steroid hormones synthesized in the brain, modulate the function of several neurotransmitter systems. The substantia nigra of the human brain expresses high concentrations of allopregnanolone (3α, 5αtetrahydroprogesterone), a neurosteroid that positively modulates the action of GABA at GABAA receptors and of 5α-dihydroprogesterone, a neurosteroid acting at the genomic level. This article reviews the roles of NS acting as neuroprotectants and as GABAA receptor agonists in the physiology and pathophysiology of the basal ganglia, their impact on dopaminergic cell activity and survival, and potential therapeutic application in PD. © 2013 Elsevier Inc.

PubMed | Experimental Neurology
Type: Journal Article | Journal: Experimental neurology | Year: 2011

Nitro-oleic acid (9- and 10-nitro-octadeca-9-enoic acid, OA-NO(2)) is an electrophilic fatty acid nitroalkene derivative that modulates gene transcription and protein function via post-translational protein modification. Nitro-fatty acids are generated from unsaturated fatty acids by oxidative inflammatory reactions and acidic conditions in the presence of nitric oxide or nitrite. Nitroalkenes react with nucleophiles such as cysteine and histidine in a variety of susceptible proteins including transient receptor potential (TRP) channels in sensory neurons of the dorsal root and nodose ganglia. The present study revealed that OA-NO(2) activates TRP channels on afferent nerve terminals in the urinary bladder and thereby increases bladder activity. The TRPV1 agonist capsaicin (CAPS, 1 M) and the TRPA1 agonist allyl isothiocyanate (AITC, 30 M), elicited excitatory effects in bladder strips, increasing basal tone and amplitude of phasic bladder contractions (PBC). OA-NO(2) mimicked these effects in a concentration-dependent manner (1 M-33 M). The TRPA1 antagonist HC3-030031 (HC3, 30 M) and the TRPV1 antagonist diaryl piperazine analog (DPA, 1 M), reduced the effect of OA-NO(2) on phasic contraction amplitude and baseline tone. However, the non-selective TRP channel blocker, ruthenium red (30 M) was a more effective inhibitor, reducing the effects of OA-NO(2) on basal tone by 75% and the effects on phasic amplitude by 85%. In bladder strips from CAPS-treated rats, the effect of OA-NO(2) on phasic contraction amplitude was reduced by 65% and the effect on basal tone was reduced by 60%. Pretreatment of bladder strips with a combination of neurokinin receptor antagonists (NK1 selective antagonist, CP 96345; NK2 selective antagonist, MEN 10,376; NK3 selective antagonist, SB 234,375, 1 M each) reduced the effect of OA-NO(2) on basal tone, but not phasic contraction amplitude. These results indicate that nitroalkene fatty acid derivatives can activate TRP channels on CAPS-sensitive afferent nerve terminals, leading to increased bladder contractile activity. Nitrated fatty acids produced endogenously by the combination of fatty acids and oxides of nitrogen released from the urothelium and/or afferent nerves may play a role in modulating bladder activity.

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