Visitor counter, Heat Map, Conversion tracking, Search Rank

Innate Immunity in ALS

These studies show that inflammation is not only the result of neurodegeneration as some have maintained but also an intrinsic part of the disease starting at the presymptomatic stage. The idea is that, unlike the acquired immune response, the innate immune response is present at or prior to the onset of the disease.

Innate immunity in amyotrophic lateral sclerosis
Although the underlying cause remains unclear, evidence suggests a role for innate immunity in disease pathogenesis. Neuroinflammation in areas of motor neuron loss is evident in presymptomatic mouse models of ALS and in human patients.

Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS.
Prior to disease onset, splenic Ly6Chi monocytes expressed a polarized macrophage phenotype (M1 signature), which included increased levels of chemokine receptor CCR2.

Progressive changes in microglia and macrophages in spinal cord and peripheral nerve in the transgenic rat model of amyotrophic lateral sclerosis.
Our study reveals an accumulation of microglia/macrophages both in the spinal cord and peripheral nerve prior to clinical onset based on CD11b tissue expression.

Appearance of phagocytic microglia adjacent to motoneurons in spinal cord tissue from a presymptomatic transgenic rat model of amyotrophic lateral sclerosis.
In this study, we revealed that activated microglia aggregated in the lumbar spinal cord of presymptomatic mutant SOD1(H46R) transgenic rats, an animal model of familial ALS.

The Neuroinflammatory Response in ALS: The Roles of Microglia and T Cells.
In the mSOD mouse, increased numbers of activated microglia are observed at early presymptomatic stages of disease, and with disease progression to end-stage, microglial numbers in the lumbar spinal cord increase further by nearly 2-fold.

Deficient GABA and Glycine Receptors in ALS

The following studies support the claim that ALS patients have deficient GABA-A alpha-1 and glycine alpha-1 receptors. Click on a title to read the abstract.

Distribution of GABAA receptor mRNA in the motor cortex of ALS patients.
The most intriguing finding was a significantly reduced mRNA expression of the alpha1-subunit in ALS patients while the level of beta1-subunit mRNA was elevated in the patients group. This may indicate specific alterations of the GABAA receptor subunit composition and result in distinct physiological and pharmacological properties of these receptors in ALS patients.

Inhibitory synaptic regulation of motoneurons: a new target of disease mechanisms in amyotrophic lateral sclerosis.
Motoneurons in these ALS mice also have insufficient synaptic inhibition as reflected by smaller GlyR currents, smaller GlyR clusters on their plasma membrane, and lower expression of GlyR1
α mRNA compared to wild-type motoneurons.

Sevoflurane and Propofol Act on GABA-A and Glycine Receptors

These studies show that sevoflurane and propofol activate and potentiate GABA-A alpha-1 and glycine alpha-1 receptors.

The role of the GABA(A) receptor alpha1 subunit N-terminal extracellular domain in propofol potentiation of chloride current.
A dose-dependent propofol potentiation of pentobarbital-induced current was observed in oocytes injected with alpha1beta3 or alpha1beta3gamma2 but not in beta3gamma2 or beta3 subunits, suggesting that the alpha1 subunit was necessary for this modulatory action of propofol. Further examination of the propofol potentiation in chimeras between the alpha1 and beta3 subunits showed that the extracellular amino-terminal half of the alpha1 subunit was sufficient to support propofol potentiation.

DrugBank: Sevoflurane
1. Gamma-aminobutyric-acid receptor subunit alpha-1
Pharmacological action: yes
Actions: agonist
2. Glycine receptor subunit alpha-1
Pharmacological action: yes
Actions: agonist

The actions of propofol on gamma-aminobutyric acid-A and glycine receptors in acutely dissociated spinal dorsal horn neurons of the rat.
Propofol was found to potentiate the functions of GABA(A)R and GlyR at the spinal level, which might contribute to propofol-induced analgesia and anesthesia.

Immune Response via GABA-A and Glycine Receptors

These studies show that immune cells have their own GABA-A and glycine receptors

Anaesthetic impairment of immune function is mediated via GABA(A) receptors.
We demonstrate, using RT-PCR, that monocytes express GABA(A) receptors constructed of 
α1, α4, β2, γ1 and/or δ subunits.
Our results show that functional GABA(A) receptors are present on monocytes with properties similar to CNS GABA(A) receptors. The functional data provide a possible explanation as to why chronic propofol and thiopental administration can increase the risk of infection in critically ill patients: their action on GABA(A) receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABA(A) receptors are insensitive to diazepam, thus the use of benzodiazepines as an alternative anesthetising agent may be advantageous where infection is a life threatening problem.

Inhibitory neurotransmitters as communication signals between the nervous and the immune systems.
GABA and glycine, and their interacting proteins, have also been described on non-neuronal cells of the nervous system, such as astrocytes and oligodendrocytes, and even outside the nervous system, e.g. on immune cells.

Inhibitory role for GABA in autoimmune inflammation
In addition to its well-known CNS roles, GABA also modulates inflammation. GABA receptor transcripts are present in immune cells (5 �7). GABA treatment decreases inflammatory cytokine production in peripheral macrophages (5). GABA and GABA type A receptor (GABA-A-R) agonists decrease cytotoxic immune responses and cutaneous delayed-type hypersensitivity reactions