Reducing l ‐lactate release from hippocampal astrocytes by intracellular oxidation increases novelty induced activity in mice

Gulf war illness (GWI), is a chronic multi-symptom illness that has impacted approximately one-third of the veterans who served in the 1990 to 1991 Gulf War. GWI symptoms include cognitive impairments (eg, memory and concentration problems), headaches, migraines, fatigue, gastrointestinal and respiratory issues, as well as emotional deficits. The exposure to neurological chemicals such as the anti-nerve gas drug, pyridostigmine bromide (PB), and the insecticide permethrin (PER), may contribute to the etiologically related factors of GWI. Various studies utilizing mouse models of GWI have reported the interplay of these chemical agents in increasing neuroinflammation and cognitive dysfunction. Astrocytes are involved in the secretion of neuroinflammatory cytokines and chemokines in pathological conditions and have been implicated in GWI symptomology. We hypothesized that exposure to PB and PER causes lasting changes to hippocampal astrocytes, concurrent with chronic cognitive deficits that can be reversed by cervical vagus nerve stimulation (VNS). GWI was induced in CD1 mice by injecting the mixture of PER (200 mg/kg) and PB (2 mg/kg), i.p. for 10 consecutive days. VNS stimulators were implanted at 33 weeks after GWI induction. The results show age-related cognitive alterations at approximately 9 months after exposure to PB and PER. The results also showed an increased number of GFAP-labeled astrocytes in the hippocampus and dentate gyrus that was ameliorated by VNS.

Download Full-text

Astrocyte Glutamate Uptake and Water Homeostasis Are Dysregulated in the Hippocampus of Multiple Sclerosis Patients With Seizures

ASN NEURO ◽

10.1177/1759091420979604 ◽

2020 ◽

Vol 12 ◽

pp. 175909142097960

Author(s):

Andrew S. Lapato ◽

Sarah M. Thompson ◽

Karen Parra ◽

Seema K. Tiwari-Woodruff

Keyword(s):

Multiple Sclerosis ◽

Mouse Model ◽

Regional Differences ◽

Neuronal Excitability ◽

Demyelinating Disease ◽

Glutamate Uptake ◽

Cx43 Expression ◽

Water Homeostasis ◽

Hippocampal Astrocytes ◽

Multiple Sclerosis Patients

While seizure disorders are more prevalent among multiple sclerosis (MS) patients than the population overall and prognosticate earlier death & disability, their etiology remains unclear. Translational data indicate perturbed expression of astrocytic molecules contributing to homeostatic neuronal excitability, including water channels (AQP4) and synaptic glutamate transporters (EAAT2), in a mouse model of MS with seizures (MS+S). However, astrocytes in MS+S have not been examined. To assess the translational relevance of astrocyte dysfunction observed in a mouse model of MS+S, demyelinated lesion burden, astrogliosis, and astrocytic biomarkers (AQP4/EAAT2/ connexin-CX43) were evaluated by immunohistochemistry in postmortem hippocampi from MS & MS+S donors. Lesion burden was comparable in MS & MS+S cohorts, but astrogliosis was elevated in MS+S CA1 with a concomitant decrease in EAAT2 signal intensity. AQP4 signal declined in MS+S CA1 & CA3 with a loss of perivascular AQP4 in CA1. CX43 expression was increased in CA3. Together, these data suggest that hippocampal astrocytes from MS+S patients display regional differences in expression of molecules associated with glutamate buffering and water homeostasis that could exacerbate neuronal hyperexcitability. Importantly, mislocalization of CA1 perivascular AQP4 seen in MS+S is analogous to epileptic hippocampi without a history of MS, suggesting convergent pathophysiology. Furthermore, as neuropathology was concentrated in MS+S CA1, future study is warranted to determine the pathophysiology driving regional differences in glial function in the context of seizures during demyelinating disease.

Download Full-text

Lactate Release from Isolated Rat Adipocytes: Influence of Cell Size, Glucose Concentration, Insulin and Epinephrine

Hormone and Metabolic Research ◽

10.1055/s-2007-1018710 ◽

1983 ◽

Vol 15 (07) ◽

pp. 326-329 ◽

Cited By ~ 51

Author(s):

D. Crandall ◽

Susan Fried ◽

A. Francendese ◽

Maria Nickel ◽

M. DiGirolamo

Keyword(s):

Cell Size ◽

Glucose Concentration ◽

Lactate Release ◽

Rat Adipocytes ◽

Isolated Rat

Download Full-text

Metformin stimulates intestinal glycolysis and lactate release: A single‐dose study of metformin in patients with intrahepatic portosystemic stent

Clinical Pharmacology & Therapeutics ◽

10.1002/cpt.2382 ◽

2021 ◽

Author(s):

Nikolaj Rittig ◽

Niels K Aagaard ◽

Elias Sundelin ◽

Gerda E Villadsen ◽

Thomas D Sandahl ◽

...

Keyword(s):

Single Dose ◽

Single Dose Study ◽

Lactate Release ◽

Dose Study

Download Full-text

Metabolic and hemodynamic responses of lower limb during exercise in patients with COPD

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.5.1573 ◽

1998 ◽

Vol 84 (5) ◽

pp. 1573-1580 ◽

Cited By ~ 100

Author(s):

François Maltais ◽

Jean Jobin ◽

Martin J. Sullivan ◽

Sarah Bernard ◽

François Whittom ◽

...

Keyword(s):

Blood Flow ◽

Lactic Acidosis ◽

Blood Lactate ◽

Lower Limb ◽

Submaximal Exercise ◽

Exercise Intolerance ◽

Early Exercise ◽

Lactate Release ◽

Leg Blood Flow ◽

Copd Patients

Premature lactic acidosis during exercise in patients with chronic obstructive pulmonary disease (COPD) may play a role in exercise intolerance. In this study, we evaluated whether the early exercise-induced lactic acidosis in these individuals can be explained by changes in peripheral O2 delivery (D˙o 2). Measurements of leg blood flow by thermodilution and of arterial and femoral venous blood gases, pH, and lactate were obtained during a standard incremental exercise test to capacity in eight patients with severe COPD and in eight age-matched controls. No significant difference was found between the two groups in leg blood flow at rest or during exercise at the same power outputs. Blood lactate concentrations and lactate release from the lower limb were greater in COPD patients at all submaximal exercise levels (all P < 0.05). LegD˙o 2at a given power output was not significantly different between the two groups, and no significant correlation was found between this parameter and blood lactate concentrations. COPD patients had lower arterial and venous pH at submaximal exercise, and there was a significant positive correlation between venous pH at 40 W and the peak O2 uptake ( r = 0.91, P < 0.0001). The correlation between venous pH and peak O2 uptake suggests that early muscle acidosis may be involved in early exercise termination in COPD patients. The early lactate release from the lower limb during exercise could not be accounted for by changes in peripheralD˙o 2. The present results point to skeletal muscle dysfunction as being responsible for the early onset of lactic acidosis in COPD.

Download Full-text

Varicella zoster virus differentially alters morphology and suppresses proinflammatory cytokines in primary human spinal cord and hippocampal astrocytes

Journal of Neuroinflammation ◽

10.1186/s12974-018-1360-9 ◽

2018 ◽

Vol 15 (1) ◽

Cited By ~ 3

Author(s):

Andrew N. Bubak ◽

Christina N. Como ◽

Anna M. Blackmon ◽

Dallas Jones ◽

Maria A. Nagel

Keyword(s):

Spinal Cord ◽

Varicella Zoster Virus ◽

Proinflammatory Cytokines ◽

Varicella Zoster ◽

Human Spinal Cord ◽

Hippocampal Astrocytes

Download Full-text

Evidence for Chloride Ions as Intracellular Messenger Substances in Astrocytes

Journal of Neurophysiology ◽

10.1152/jn.1999.82.1.248 ◽

1999 ◽

Vol 82 (1) ◽

pp. 248-254 ◽

Cited By ~ 21

Author(s):

Lane K. Bekar ◽

Wolfgang Walz

Keyword(s):

Brain Tissue ◽

Spreading Depression ◽

Receptor Activation ◽

Chloride Ions ◽

Whole Cell ◽

Astrocytic Swelling ◽

Hippocampal Astrocytes ◽

Muscimol Binding ◽

Intracellular Messenger

Cultured rat hippocampal astrocytes were used to investigate the mechanism underlying the suppression of Ba2+-sensitive K+ currents by GABAAreceptor activation. Muscimol application had two effects on whole cell currents: opening of the well-known Cl− channel of the GABAA receptor and a secondary longer-lasting blockade of outward K+ currents displaying both peak and plateau phases. This blockade was independent of both Na+ (inside and outside) and ATP in the pipette. It also seemed to be independent of muscimol binding to the receptor because picrotoxin application showed no effect on the K+ conductance. The effect is blocked when anion efflux is prevented by replacing Cl−with gluconate (both inside and out) and is enhanced with more permeant anions such as Br− and I−. Moreover, the effect is reproduced in the absence of muscimol by promoting Cl− efflux via lowering of extracellular Cl−levels. These results, along with the requirement for Cl−efflux in muscimol experiments, show a strong dependency of the secondary blockade on Cl− efflux through the Cl− channel of the GABAA receptor. We therefore conclude that changes in the intracellular Cl−concentration alter the outward K+ conductances of astrocytes. Such a Cl−-mediated modulation of an astrocytic K+ conductance will have important consequences for the progression of spreading depression through brain tissue and for astrocytic swelling in pathological situations.

Download Full-text