Distribution of GABA A and GABA B receptors in mammalian brain: Potential targets for drug development

GABA is the major inhibitory neurotransmitter in mammalian brain. GABA receptors and the metabolism of GABA are significant targets for new centrally acting drugs to treat neurological and behavioral disorders. The simple neutral amino acid is likely to subserve a neurotransmitter role at 25–50% of all synapses in the central nervous system. GABA's actions are mediated by two different receptors, GABA A and GABA B receptors. GABA A receptors are ligand-gated chloride channels that are sensitive to the convulsant alkaloid bicuculline and modulated by benzodiazepines and barbiturates. GABA B receptors affect calcium and potassium conductance through GTP binding proteins and are insensitive to bicuculline and sensitive to the agonist baclofen. Both receptors are widely distributed in cerebral cortex, hippocampus, basal ganglia, thalamus, cerebellum, and brainstem.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50215/1/430210303_ftp.pd

Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice.

Mutations in SLURP1 cause mal de Meleda, a rare palmoplantar keratoderma (PPK). SLURP1 is a secreted protein that is expressed highly in keratinocytes but has also been identified elsewhere (e.g., spinal cord neurons). Here, we examined Slurp1-deficient mice (Slurp1(-/-)) created by replacing exon 2 with β-gal and neo cassettes. Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect. In addition, Slurp1(-/-) mice exhibited reduced adiposity, protection from obesity on a high-fat diet, low plasma lipid levels, and a neuromuscular abnormality (hind-limb clasping). Initially, it was unclear whether the metabolic and neuromuscular phenotypes were due to Slurp1 deficiency, because we found that the targeted Slurp1 mutation reduced the expression of several neighboring genes (e.g., Slurp2, Lypd2). We therefore created a new line of knockout mice (Slurp1X(-/-) mice) with a simple nonsense mutation in exon 2. The Slurp1X mutation did not reduce the expression of adjacent genes, but Slurp1X(-/-) mice exhibited all of the phenotypes observed in the original line of knockout mice. Thus, Slurp1 deficiency in mice elicits metabolic and neuromuscular abnormalities in addition to PPK

Myoclonus in adult Huntington's disease

Two brothers with clinically definite adult Huntington's disease developed disabling myoclonus years after the first signs of the disease. Their electroencephalograms were consistent with a primary generalized epilipsy, although neither man had seizures. The myoclonus was controlled with valproic acid therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50341/1/410290217_ftp.pd

GABA as the pallidothalamic neurotransmitter: implications for basal ganglia function

GABA levels, high affinity GABA uptake and glutamic acid decarboxylase levels are reduced in rat ventroanterolateral thalamic nucleus after destruction of the entopeduncular nucleus with kainic acid. This is strong evidence that GABA is an entopedunculothalamic neurotransmitter. The striatoentopeduncular pathway is also GABAergic. Thus the function of the corpus striatum may be to disinhibit the thalamus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24459/1/0000733.pd

Incorporation of MMP inhibitors into dental adhesive systems and bond strength of coronal composite restorations: A systematic review and meta-analysis of in vitro studies

PURPOSE: To systematically review in vitro studies that incorporated MMP inhibitors into adhesive systems in terms of the effect on immediate and aged bond strength of dental composite to dentine. MATERIALS AND METHODS: Independently, two reviewers conducted an electronic search in three databases (MEDLINE, EMBASE, and Google Scholar) following the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P), up to 6 March 2022. RESULTS: The search resulted in 894 papers, 33 of which were eligible to be included in the review; of those, 13 fulfilled the meta-analysis eligibility criteria. Nineteen inhibitors were used among the studies, and those included in the meta-analysis were 2%, 0.2% chlorhexidine (CHX), 5 µM GM1489, and 0.5%, 1% benzalkonium chloride (BAC). In the meta-analysis, while above inhibitors showed no adverse effect on bond strength, 0.2% CHX and 5 µM GM1489 caused a significant increase in immediate and 12-months bond strength. All other inhibitors resulted in a significant increase in bond strength at six months of ageing. CONCLUSIONS: Incorporation of MMP inhibitors into the adhesive system has no unfavourable effect on immediate bond strength but a favourable effect on longer-term bond strength. Additionally, inhibitors other than CHX could have similar or better effects on bond strength

Excitatory amino acids and Alzheimer's disease

Excitatory amino acids (EAA) such as glutamate and aspartate are major transmitters of the cerebral cortex and hippocampus and EAA mechanisms appear to play a role in learning and memory. Anatomical and biochemical evidence suggests that there is both pre- and postsynaptic disruption of EAA pathways in Alzheimer's disease. Dysfunction of EAA pathways could play a role in the clinical manifestations of Alzheimer's disease, such as memory loss and signs of cortical disconnection. Furthermore, EAA might be involved in the pathogenesis of Alzheimer's disease, by virtue of their neurotoxic (excitotoxic) properties. Circumstantial evidence raises the possibility that the EAA system may partially determine the distribution of pathology in Alzheimer's disease and may be important in producing the neurofibrillary tangles, RNA reductions and dendritic changes which characterize this devastating disorder. In this article, we will review the evidence suggesting a role for EAA in the clinical manifestations and pathogenesis of Alzheimer's disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27793/1/0000191.pd

Synaptic localization of striatal NMDA, quisqualate and kainate receptors

Striatal binding of labeled glutamate to (NMDA) receptors, -[alpha]-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) to quisqualate receptors and kainate to kainate receptors was examined in rats which had received unilateral decortications or unilateral striatal quinolinic acid lesions. One week after decortication, there were no significant changes in NMDA, quisqualate or kainate receptors in the striatum ipsilateral to the lesion, when compared to the striatum contralateral to the lesion. In contrast, binding to NMDA receptors was reduced by 92 %, to quisqualate receptors by 80 % and to kainate receptors by 81 % in striatum 3 months after quinolinic acid lesions. The reduction in NMDA receptor binding was significantly greater than the loss of quisqualate or kainate receptors. These results suggest that NMDA, quisqualate and kainate receptor recognition sites are located postsynaptically in the striatum. These results also have implications for the quinolinic acid model of Huntington's disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27879/1/0000293.pd

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Pharmacology of GABA-mediated inhibition of spinal cord neurons in vivo and in primary dissociated cell culture

In this paper it is shown that the postsynaptic GABA-receptor chloride ion channel complex is composed of several functional subunits. There are probably at least two stereospecific locations on the receptor for GABA-binding and both must be occupied to obtain an increase in chloride conductance. The interaction between these sites is uncertain but there could be either positive cooperativity between the sites or only a requirement that both sites are occupied without occupation of either site affecting the affinity for GABA of the other site. There is a chloride conductance channel coupled to the GABA receptor which opens for an average of 20 msec and has an average conductance of 18 pS. The GABA-coupled chloride channel may or may not have the same composition as the glycine coupled chloride channel.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45345/1/11010_2004_Article_BF00235693.pd