a-new-method-for-inducing-a-depression-like-behavior-in-rats

A New Method for Inducing a Depression-Like Behavior in Rats

Contagious depression is a phenomenon that is yet to be fully recognized and this stems from insufficient material on the subject. At the moment, there is ...

a-middle-cerebral-artery-occlusion-technique-for-inducing-post-stroke

A Middle Cerebral Artery Occlusion Technique for Inducing Post-stroke Depression in Rats

Post-stroke depression (PSD) is the most recurrent of all psychiatric complications resulting from an ischemic stroke. A greater majority (about 60%) of ...

inducing-acute-liver-injury-rats-via-carbon-tetrachloride-ccl4

Inducing Acute Liver Injury in Rats via Carbon Tetrachloride (CCl<sub>4</sub>) Exposure Through an Orogastric Tube

Acute liver injury (ALI) plays a crucial role in the development of hepatic failure, which is characterized by severe liver dysfunction including ...

laser-induced-brain-injury-in-the-motor-cortex-of-rats

Laser-Induced Brain Injury in the Motor Cortex of Rats

A common technique for inducing stroke in experimental rodent models involves the transient (often denoted as MCAO-t) or permanent (designated as MCAO-p) ...

induction-diffuse-axonal-brain-injury-rats-based-on-rotational

Induction of Diffuse Axonal Brain Injury in Rats Based on Rotational Acceleration

Traumatic brain injury (TBI) is a major cause of death and disability. Diffuse axonal injury (DAI) is the predominant mechanism of injury in a large ...

measuring-post-stroke-cerebral-edema-infarct-zone-blood-brain-barrier

Measuring Post-Stroke Cerebral Edema, Infarct Zone and Blood-Brain Barrier Breakdown in a Single Set of Rodent Brain Samples

One of the most common causes of morbidity and mortality worldwide is ischemic stroke. Historically, an animal model used to stimulate ischemic stroke ...

a-complex-diving-for-food-task-to-investigate-social-organization

A Complex Diving-For-Food Task to Investigate Social Organization and Interactions in Rats

For many species, where status is a vital motivator that can affect health, social hierarchies influence behavior. Social hierarchies that include ...

Ben-Gurion University of the Negev

In previous studies, we have shown that by increasing the brain-to-blood glutamate efflux upon scavenging blood glutamate with either oxaloacetate or pyruvate, one achieves highly significant neuroprotection particularly in the context of traumatic brain injury. The current study examines, for the first time, how the blood glutamate scavenging properties of glutamate-pyruvate transaminase (GPT), alone or in combination with pyruvate, may contribute to the spectrum of its neuroprotective mechanisms and improve the outcome of rats exposed to brain ischemia, as they do after head trauma. Rats that were exposed to permanent middle cerebral artery occlusion (MCAO) and treated with intravenous 250 mg/kg pyruvate had a smaller volume of infarction and reduced brain edema, resulting in an improved neurological outcome and reduced mortality compared to control rats treated with saline. Intravenous pyruvate at the low dose of 31.3 mg/kg did not demonstrate any neuroprotection. However, when combined with 0.6 mg/kg of GPT there was a similar neuroprotection observed as seen with pyruvate at 250 mg/kg. Animals treated with 1.69 g/kg glutamate had a worse neurological outcome and a larger extent of brain edema. The decrease in mortality, infarcted brain volume and edema, as well as the improved neurological outcome following MCAO, was correlated with a decrease in blood glutamate levels. We therefore suggest that the blood glutamate scavenging activity of GPT and pyruvate contributes to the spectrum of their neuroprotective mechanisms and may serve as a new neuroprotective strategy for the treatment of ischemic stroke.

Pyruvate's blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms in a rat model of stroke.

The exact mechanism of hypothermia-induced neuroprotection has not been determined yet; however, we hypothesized that it may be mediated by a blood glutamate-scavenging effect. Here, we examine the effect of hypothermic conditions (mild, moderate, and deep) on blood glutamate levels in naive rats. To identify the mechanism of hypothermia-induced glutamate reduction, we also measured concentrations of glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT), the primary regulators of glutamate concentration in blood.

The role of hypothermia in the regulation of blood glutamate levels in naive rats.

Excessive concentrations of L-glutamate (glutamate) have been found to posses neurotoxic properties. This study investigates how stress induced by strong physical exercise effects blood glutamate, 2-ketoglutarate, Alanine aminotransferase (ALT) and Aspartate Aminotransferase (AST) levels. The relationship between muscle damage caused by strong physical exercise and blood glutamate levels was also examined. Twenty-two healthy volunteers engaged in intense veloergometry ("spinning") for a duration of 60 minutes. Two 10 minute peaks of extremely intense exercise were performed at 10 minutes and 50 minutes after the start of exercise. After 60 minutes of exercise, volunteers were monitored for an additional 180 minutes in resting conditions. Blood samples for determination of glutamate and 2-ketoglutarate levels were collected prior to exercise and then every 30 min for entire experiment. Blood samples were also taken at those time points to measure glutamate, 2-ketoglutarate, AST, ALT, creatine phosphokinase (CPK), myoglobin, lactate and venous blood gas levels. Blood glutamate levels were significantly elevated throughout the exercise session (P less than 0.001) and then returned to baseline levels at the cessation of exercise. 2-ketoglutarate, a product of glutamate metabolism, reached significantly elevated levels at 30 minutes (P less than 0.01) from the start of exercise and remained elevated up to 240 minutes post exercise initiation (P less than 0.001). AST and ALT levels were elevated at 60 minutes when compared to baseline. AST levels remained elevated at 240 minutes, unlike ALT levels which returned to baseline values at 240 minutes. Strong physical exercise leads to a significant elevation in blood glutamate, most likely as a result of skeletal muscle damage. 2-ketoglutarate was also found to be elevated for long periods of time, reflecting an ongoing process of glutamate breakdown. Elevated concentrations of AST and ALT in plasma reflect the importance of these enzymes in the maintenance of stable blood glutamate concentrations.

Effects of strong physical exercise on blood glutamate and its metabolite 2-ketoglutarate levels in healthy volunteers.

Post-stroke depression (PSD) is the most frequent psychiatric complication following ischemic stroke. It affects up to 60% of all patients and is associated with increased morbidity and mortality following ischemic stroke. The pathophysiology of PSD remains elusive and appears to be multifactorial, rather than "purely" biological or psychosocial in origin. Thus, valid animal models of PSD would contribute to the study of the etiology (and treatment) of this disorder.

Biological and Behavioral Patterns of Post-Stroke Depression in Rats.

Stroke plays a role in high morbidity and mortality. Deciphering its mechanisms and pathophysiology is critical for the creation of new drugs and therapies. Most of the previous animal models of stroke, aimed at identifying the extent and location of brain injury following stroke, require animal sacrifice, which, besides ethical considerations, also negates the ability for follow up studies with the same rats. Because of these failures, the useof clinicalmagnetic resonance scanners forevaluatingsmall animal models has been increasing. Magnetic resonance imaging scanners used particularly for small-bore animals are eligible for use in high-resolution magnetic resonance imaging of rodent brains. However, high costs and scarcity factor heavily in the rare availability of these scanners. In our investigation, we sought to establish a unitary magnetic resonance imaging protocol for stroke assessment in rats. We made use of a 3-Tesla magnetic resonance imaging clinical scanner, as well as another clinical equipment, with the purpose of increasing its reproducibility. The results of inquest validated a new magnetic resonance imaging protocol, comparing a magnetic resonance imaging-measured infarcted zone to the "gold standard" of histological examination. We carried out the experimental procedure on a 3 Tesla magnetic resonance imaging clinical scanner using a conventional eight-channel receive-only coil. The two methods produced remarkable quantitative and qualitative correlations between them. Conclusively, we showed the clinical magnetic resonance imaging scanner to be a high-precision and sensitive image analysis instrument for evaluating both the infarct zone and the brain edema in a stroke experimental rat model.

Establishment of Novel Technical Methods for Evaluating Brain Edema and Lesion Volume in Stroked Rats: a Standardization of Measurement Procedures.

A common experimental rodent model for stroke includes induction by a technique in which middle cerebral artery is transiently (MCAO-t) or permanently (MCAO-p) occluded by catheterization. However, this model has prominent disadvantages which consist of the high variability of localization and size of the ischemic area, cases of intracranial hemorrhage and high mortality. Furthermore, the duration of a single MCAO operation takes about thirty minutes and requires highly trained staff. In this article, we propose an alternative method, which is based on laser-induced stroke in the motor cortex. In our research, we compared the original MCAO-p and MCAO-t models and a novel laser model.

An Alternative Model of Laser-Induced Stroke in the Motor Cortex of Rats.

Post-stroke depression (PSD) is a common and serious complication following stroke. Both stroke and depression have independently been associated with pathologically elevated glutamate levels in the brain's extra-cerebral fluid (ECF). Here we evaluate an alternative therapeutic approach to PSD with pyruvate. Rats were randomly assigned into one of 3 groups: Middle Cerebral Artery Occlusion (MCAO) plus pyruvate treatment, MCAO plus placebo treatment, and sham operated rats. Post-MCAO depressive and anxiety-like behavior was assessed, along with neurological status, brain infarct zone, brain edema, blood brain barrier (BBB) breakdown, cerebrospinal fluid and blood glutamate levels. Anxiety-like behavior and levels of blood alanine and α-ketoglutarate were measured in naïve rats treated with pyruvate, as a control. Post-stroke neurological deficit with concurrent elevation in glutamate levels were demonstrated, with peak glutamate levels 24 h after MCAO. Treatment with pyruvate led to reduced glutamate levels 24 h after MCAO and improved neurologic recovery. Pyruvate treatment reduced lesion volume, brain edema and the extent of BBB permeability 24 h post-MCAO. Naïve rats treated with pyruvate showed increased levels of α-ketoglutarate. Rats demonstrated post-stroke depressive behavior that was improved by the administration of pyruvate. There was less anxiety-like behavior in post-stroke rats treated with placebo in comparison to the post-stroke rats treated with pyruvate or sham operated rats. Glutamate scavenging with pyruvate appears to be an effective as a method in providing neuroprotection following stroke and as a therapeutic option for the treatment of PSD by reducing the consequent elevations in CNS glutamate levels.

The effect of pyruvate on the development and progression of post-stroke depression: A new therapeutic approach.

Maternal-deprivation of rodent pups is a relevant model of extreme early-life stress that can be relevant to the understanding of long-term effects of war, migration, parental loss and displacement. Although even mild stress during infancy affects brain development and behavior, the current study focused on the effects of six hour daily maternal-separation, a model that reflects the severe distress often experienced in those circumstances. This study emphasizes the effect of maternal separation on social behavior in the context of a variety of factors that measure cognitive and emotional behavior which were subject to principle component analysis. Sprague-Dawley pups were separated from the dam for 6 h each day during the first 3-weeks of life and underwent a battery of behavioral tests at 3-months of age. We found that rodents exposed to postnatal maternal deprivation displayed submissive behavior in resident-intruder and dominant-submissive tests, as well as significantly more anxiety and anhedonia than control rats. The results of multivariate statistical analysis show that the dominant-submissive behavior correlates with depressive, anxiety and social behavior and can be predicted with an accuracy of 86.2%. The increased submissive behavior in male rats that had been subjected to severe postnatal stress suggests that exposure to stress during infancy and childhood could have long-term effects on social relationships. The mechanism of the long-term effects on depression, anxiety and submissive behavior requires further investigation.

Early life stress induces submissive behavior in adult rats.

Stroke is a major cause of global morbidity and mortality. Middle cerebral artery occlusion (MCAO) has historically been the most common animal model of simulating ischemic stroke. The extent of neurological injury after MCAO is typically measured by cerebral edema, infarct zone, and blood-brain barrier (BBB) permeability. A significant limitation of these methods is that separate sets of brains must be used for each measurement. Here we examine an alternative method of measuring cerebral edema, infarct zone and BBB permeability following MCAO in the same set of brain samples. Ninety-six rats were randomly divided into three experimental groups. Group 1 ( = 27) was used for the evaluation of infarct zone and brain edema in rats post-MCAO ( = 17) vs. sham-operated controls ( = 10). Group 2 ( = 27) was used for the evaluation of BBB breakdown in rats post-MCAO ( = 15) vs. sham-operated controls ( = 10). In Group 3 ( = 42), all three parameters were measured in the same set of brain slices in rats post-MCAO ( = 26) vs. sham-operated controls ( = 16). The effect of Evans blue on the accuracy of measuring infarct zone by 2,3,5-triphenyltetrazolium chloride (TTC) staining was determined by measuring infarct zone with and without an applied blue filter. The effects of various concentrations of TTC (0, 0.05, 0.35, 0.5, 1, and 2%) on the accuracy of measuring BBB permeability was also assessed. There was an increase in infarct volume ( < 0.01), brain edema ( < 0.01) and BBB breakdown ( < 0.01) in rats following MCAO compared to sham-operated controls, whether measured separately or together in the same set of brain samples. Evans blue had an effect on measuring infarct volume that was minimized by the application of a blue filter on scanned brain slices. There was no difference in the Evans blue extravasation index for the brain tissue samples without TTC compared to brain tissue samples incubated in TTC. Our results demonstrate that measuring cerebral edema, infarct zone and BBB permeability following MCAO can accurately be measured in the same set of brain samples.

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Publication title Cited by 23	2018
Publication title Cited by 11	2019
Publication title Cited by 18	2020
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Publication title Cited by 8	2020

Article	Year
Pyruvate's blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms in a rat model of stroke. The European journal of neuroscience\| PubMed ID: 21936878	2011
The role of hypothermia in the regulation of blood glutamate levels in naive rats. Journal of neurosurgical anesthesiology\| PubMed ID: 23295267	2013
Effects of strong physical exercise on blood glutamate and its metabolite 2-ketoglutarate levels in healthy volunteers. Acta neurobiologiae experimentalis\| PubMed ID: 23377269	2012
Biological and Behavioral Patterns of Post-Stroke Depression in Rats. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques\| PubMed ID: 29880078	2018
Establishment of Novel Technical Methods for Evaluating Brain Edema and Lesion Volume in Stroked Rats: a Standardization of Measurement Procedures. Brain research\| PubMed ID: 31026458	2019
An Alternative Model of Laser-Induced Stroke in the Motor Cortex of Rats. Biological procedures online\| PubMed ID: 31130825	2019
The effect of pyruvate on the development and progression of post-stroke depression: A new therapeutic approach. Neuropharmacology\| PubMed ID: 31153808	2019
Early life stress induces submissive behavior in adult rats. Behavioural brain research\| PubMed ID: 31254880
A Novel Method for Assessing Cerebral Edema, Infarcted Zone and Blood-Brain Barrier Breakdown in a Single Post-stroke Rodent Brain. Frontiers in neuroscience\| PubMed ID: 31680838	2019

Ruslan Kuts

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