The Role of NMDA Receptor Partial Antagonist, Carbamathione, as a Therapeutic Agent for Transient Global Ischemia.

Carbamathione (Carb), an NMDA glutamate receptor partial antagonist, has potent neuroprotective functions against hypoxia- or ischemia-induced neuronal injury in cell- or animal-based stroke models. We used PC-12 cell cultures as a cell-based model and bilateral carotid artery occlusion (BCAO) for stroke. Whole-cell patch clamp recording in the mouse retinal ganglion cells was performed.

The role of G-CSF neuroprotective effects in neonatal hypoxic-ischemic encephalopathy (HIE): current status.

Hypoxic-ischemic encephalopathy (HIE) is an important cause of permanent damage to central nervous system (CNS) that may result in neonatal death or manifest later as mental retardation, epilepsy, cerebral palsy, or developmental delay. The primary cause of this condition is systemic hypoxemia and/or reduced cerebral blood flow with long-lasting neurological disabilities and neurodevelopmental impairment in neonates. About 20 to 25% of infants with HIE die in the neonatal period, and 25-30% of survivors are left with permanent neurodevelopmental abnormalities.

Granulocyte-colony stimulating factor gene therapy as a novel therapeutics for stroke in a mouse model.

Background: Global ischemia is the resulting effect of a cardiopulmonary arrest (CPA). Presently there is no effective treatment to address neurological deficits in patients who survived a CPA. Granulocyte-colony stimulating factor is a growth factor (G-CSF) with a plethora of beneficial effects, including neuroprotection.

G-CSF attenuates neuroinflammation and neuronal apoptosis via the mTOR/p70SK6 signaling pathway in neonatal Hypoxia-Ischemia rat model.

Background: Hypoxic-ischemic encephalopathy (HIE) is an important cause of permanent damage to the central nervous system, associated with long-lasting neurological disabilities and neurodevelopmental impairment in neonates. Granulocyte-colony stimulating factor (G-CSF) has been shown to have neuroprotective activity in a variety of experimental brain injury models and G-CSF is a standard treatment in chemotherapeutic-induced neutropenia. The underlying mechanisms are still unclear.

Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model.

Background: The FDA approved drug granulocyte-colony stimulating factor (G-CSF) displays anti-apoptotic and immunomodulatory properties with neurogenesis and angiogenic functions. It is known to demonstrate neuroprotective mechanisms against ischemic global stroke. Autophagy is a method for the degradation of intracellular components and in particular, unrestrained autophagy may lead to uncontrolled digestion of affected neurons as well as neuronal death in cerebral ischemia.

A New Neural Pathway from the Ventral Striatum to the Nucleus Basalis of Meynert with Functional Implication to Learning and Memory.

The cholinergic neurons in the nucleus basalis of Meynert (NBM) are among the first group of neurons known to become degenerated in Alzheimer's disease, and thus the NBM is proposed to be involved in learning and memory. The marginal division (MrD) of the striatum is a newly discovered subdivision at the ventromedial border of the mammalian striatum and is considered to be one part of the ventral striatum involved in learning and memory. The present study provided evidence to support the hypothesis that the MrD and the NBM were structurally connected at cellular and subcellular levels with functional implications in learning and memory.

Granulocyte-colony stimulating factor protects against endoplasmic reticulum stress in an experimental model of stroke.

Granulocyte-colony stimulating factor (G-CSF) is an endogenous growth factor that exhibits a diverse range of neuroprotective mechanisms against a variety of neurological disorders including ischemic stroke. We investigated the anti-apoptotic mechanisms of G-CSF against endoplasmic reticulum (ER) stress induced apoptosis. Sprague-Dawley rats were subjected to transient occlusion of the middle cerebral artery (MCAO) for 90 min.

Preparation, Stimulation and Other Uses of Adult Rat Brain Synaptosomes.

In this paper, our protocol for preparation of brain synaptosomes is described. Synaptosomes are a valuable model system for analysis of structural components of the synapse as well as for investigation of synaptic function. Synaptosomal preparations are necessary for understanding molecular changes at synapses where critical post-translational modifications of synaptic proteins may occur.

Analysis of Neuroprotection by Taurine and Taurine Combinations in Primary Neuronal Cultures and in Neuronal Cell Lines Exposed to Glutamate Excitotoxicity and to Hypoxia/Re-oxygenation.

Ischemic stroke is one of the greatest contributors to death and long term disability in developed countries. Ischemia induced brain injury arises due to excessive release of glutamate and involves cell death due to apoptosis and endoplasmic reticulum (ER) stress responses. Despite major research efforts there are currently no effective treatments for stroke.

Neuroprotective Functions Through Inhibition of ER Stress by Taurine or Taurine Combination Treatments in a Rat Stroke Model.

Taurine, as a free amino acid, is found at high levels in many tissues including brain, heart and skeletal muscle and is known to demonstrate neuroprotective effects in a range of disease conditions including stroke and neurodegenerative disease. Using in vitro culture systems we have demonstrated that taurine can elicit protection against endoplasmic reticulum stress (ER stress) from glutamate excitotoxicity or from excessive reactive oxygen species in PC12 cells or rat neuronal cultures. In our current investigation we hypothesized that taurine treatment after stroke in the rat middle cerebral artery occlusion (MCAO) model would render protection against ER stress processes as reflected in decreased levels of expression of ER stress pathway components.

Role of Mitochondria and Endoplasmic Reticulum in Taurine-Deficiency-Mediated Apoptosis.

Taurine is a ubiquitous sulfur-containing amino acid found in high concentration in most tissues. Because of its involvement in fundamental physiological functions, such as regulating respiratory chain activity, modulating cation transport, controlling inflammation, altering protein phosphorylation and prolonging lifespan, taurine is an important nutrient whose deficiency leads to severe pathology and cell death. However, the mechanism by which taurine deficiency causes cell death is inadequately understood.

Dr. Eugene Roberts.

This is an obituary for Eugene Roberts (1920-2016), an outstanding neurobiochemist who was the first to report on the discovery of gamma-aminobutyric acid (GABA) in the brain, and whose research focused on the important role of GABA in human health and disease.

Activation of Brain L-glutamate Decarboxylase 65 Isoform (GAD65) by Phosphorylation at Threonine 95 (T95).

Protein phosphorylation plays an important role in regulating soluble L-glutamic acid decarboxylase (GAD) and membrane-associated GAD activity. Previously, we reported the effect of phosphorylation on the two well-defined GAD isoforms, namely, GAD65 and GAD67, using highly purified preparations of recombinant human brain GAD65 (hGAD65) and GAD67. GAD65 was activated by phosphorylation, while GAD67 was inhibited by phosphorylation.

Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases.

In stroke and neurodegenerative disease, neuronal excitotoxicity, caused by increased extracellular glutamate levels, is known to result in calcium overload and mitochondrial dysfunction. Mitochondrial deficits may involve a deficiency in energy supply as well as generation of high levels of oxidants which are key contributors to neuronal cell death through necrotic and apoptotic mechanisms. Excessive glutamate receptor stimulation also results in increased nitric oxide generation which can be detrimental to cells as nitric oxide interacts with superoxide to form the toxic molecule peroxynitrite.

Regulation of GABA Neurotransmission by Glutamic Acid Decarboxylase (GAD).

Control of GABA neurotransmission at the pre-synaptic site occurs substantially through the activation of the glutamic acid decarboxylase (GAD) enzymes GAD65 and GAD67. Concentrations of GAD65 and GAD67 are controlled either by transcription or by mRNA splicing and importantly the activities of these key enzymes are regulated by post-translational mechanisms. Important post-translational modifications include proteolytic cleavage, phosphorylation and palmitoylation.

The marginal division of the striatum and hippocampus has different role and mechanism in learning and memory.

The memory function of the hippocampal formation (Hip) and the marginal division (MrD) of neostriatum was compared. Rats with bilateral lesions of the MrD either immediate or 24 h after training in Y-maze were found to have decrease in correct runs in both groups. However, animals with transected afferent and efferent nerve bundles to isolate the Hip immediately or 24 h after training in Y-maze were found to show a decrease in correct runs only in the group injured immediately after Y-maze training but not in the 24 h group suggesting that MrD is likely involved in the entire process of long-term memory consolidation whereas the Hip only contributes to memory in the early stage.

Protective mechanism of sulindac in an animal model of ischemic stroke.

Background And Purpose: The present study analyzed whether administration of sulindac, a non-steroidal anti-inflammatory drug (NSAID) would prevent, attenuate or repair ischemia induced brain injury and reverse functional impairment in a focal ischemia model of stroke.

Methods: Male Sprague-Dawley rats (weight 250-300 g) were subjected to middle cerebral artery occlusion (MCAO). Sulindac was given 2 days before and 24 h after ischemia at 0.

Mode of action of S-methyl-N, N-diethylthiocarbamate sulfoxide (DETC-MeSO) as a novel therapy for stroke in a rat model.

One approach for protecting neurons from excitotoxic damage in stroke is to attenuate receptor activity with specific antagonists. S-Methyl-N, N-diethylthiocarbamate sulfoxide (DETC-MeSO), the active metabolite of disulfiram, has been shown to be a partial antagonist of glutamate receptors and effective in reducing seizure. First, we investigated neuroprotective effect of DETC-MeSO on primary cortical neuronal culture under hypoxia/reoxygenation condition in vitro.

Taurine exerts robust protection against hypoxia and oxygen/glucose deprivation in human neuroblastoma cell culture.

Stroke is one of the leading causes of mortality and disability worldwide. There is no effective treatment for stroke despite extensive research. Taurine is a free amino acid which is present at high concentrations in a range of organs including the brain, heart, and retina in mammalian systems.

Taurine and its neuroprotective role.

Taurine plays multiple roles in the CNS including acting as a -neuro-modulator, an osmoregulator, a regulator of cytoplasmic calcium levels, a trophic factor in development, and a neuroprotectant. In neurons taurine has been shown to prevent mitochondrial dysfunction and to protect against endoplasmic reticulum (ER) stress associated with neurological disorders. In cortical neurons in culture taurine protects against excitotoxicity through reversing an increase in levels of key ER signaling components including eIF-2-alpha and cleaved ATF6.

The mechanism of taurine protection against endoplasmic reticulum stress in an animal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culture.

Taurine is an inhibitory neurotransmitter and is one of the most abundant amino acids present in the mammalian nervous system. Taurine has been shown to provide protection against neurological diseases, such as Huntington's disease, Alzheimer's disease, and stroke. Ischemic stroke is one of the leading causes of death and disability in the world.

Neuroprotective Mechanisms of Taurine against Ischemic Stroke.

Ischemic stroke exhibits a multiplicity of pathophysiological mechanisms. To address the diverse pathophysiological mechanisms observed in ischemic stroke investigators seek to find therapeutic strategies that are multifaceted in their action by either investigating multipotential compounds or by using a combination of compounds. Taurine, an endogenous amino acid, exhibits a plethora of physiological functions.

Taurine and central nervous system disorders.

In the present era, investigators seek to find therapeutic interventions that are multifaceted in their mode of action. Such targets provide the most advantageous routes for addressing the multiplicity of pathophysiological avenues that lead to neuronal dysfunction and death observed in neurological disorders and neurodegenerative diseases. Taurine, an endogenous amino acid, exhibits a plethora of physiological functions in the central nervous system.