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1.
Exp Brain Res ; 134(1): 58-65, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11026726

ABSTRACT

The proinflammagen lipopolysaccharide (LPS) was infused chronically (37 days) into the basal forebrain of rats. The current study determined whether the chronic administration of either a non-competitive N-methyl-D-aspartate- (NMDA-) sensitive receptor antagonist, memantine, or a selective cyclooxygenase-2 (COX2)/lipoxygenase inhibitor, CI987, could provide significant neuroprotection from the cytotoxic effects of LPS-induced neuroinflammation. Chronic LPS infusions decreased cortical choline acetyltransferase activity, which paralleled a decline in the number of choline-acetyltransferase-immunoreactive-cells within the basal forebrain as well as the number of activated resident microglia. The infusions appeared to be selective for cholinergic neurons. Peripheral administration of memantine (i.p.) or CI987 (s.c.) significantly attenuated the cytotoxic effects of the chronic inflammatory processes upon cholinergic cells within the basal forebrain. However, only CI987 attenuated the neuroinflammation produced by LPS and the subsequent changes in microglial activation. These results indicate that the cytotoxic effects of chronic neuroinflammation may involve prostanoid synthesis and may operate through NMDA receptors, and that the effects of prostaglandins occur upstream to NMDA-receptor activation.


Subject(s)
Cholinergic Fibers/enzymology , Encephalitis/drug therapy , Encephalitis/physiopathology , Glutamic Acid/metabolism , Isoenzymes/antagonists & inhibitors , Acetylcholine/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cholinergic Fibers/chemistry , Cholinergic Fibers/drug effects , Chronic Disease , Cyclooxygenase 2 , Encephalitis/enzymology , Excitatory Amino Acid Antagonists/pharmacology , Image Cytometry/methods , Isoenzymes/metabolism , Male , Memantine/pharmacology , Nerve Tissue Proteins/analysis , Phenols/pharmacology , Prosencephalon/cytology , Prosencephalon/enzymology , Prosencephalon/immunology , Prostaglandin-Endoperoxide Synthases/metabolism , Radioimmunoassay , Rats , Rats, Inbred F344 , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Thiazoles/pharmacology
2.
Neuroscience ; 88(1): 193-200, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10051200

ABSTRACT

Inflammatory processes may play a critical role in the degeneration of basal forebrain cholinergic cells that underlies some of the cognitive impairments associated with Alzheimer's disease. In the present study, the proinflammagen lipopolysaccharide, from the cell wall of Gram-negative bacteria, was used to produce inflammation within the basal forebrain of rats. The effects of acute, high-dose injections of lipopolysaccharide (2, 20 or 40 microg) upon basal forebrain chemistry and neuronal integrity were compared with the effects of chronic, low-dose lipopolysaccharide infusions (0.18, 0.25, 1.8 or 5.0 microg/h) for either 14, 37, 74 or 112 days. Acute exposure to lipopolysaccharide decreased cortical choline acetyltransferase activity and the number of immunoreactive choline acetyltransferase-positive cells within a small region of the basal forebrain. Regional levels of five different neuropeptides were unchanged by acute, high-dose lipopolysaccharide injections. Chronic lipopolysaccharide infusions produced (i) a time-dependent, but not dose-dependent, decrease in cortical choline acetyltransferase activity that paralleled a decline in the number of choline acetyltransferase- and p75-immunoreactive cells within the basal forebrain, and (ii) a dense distribution of reactive astrocytes and microglia within the basal forebrain. Chronic neuroinflammation might underlie the genesis of some neuropathological changes associated with normal ageing or Alzheimer's disease.


Subject(s)
Choline O-Acetyltransferase/metabolism , Inflammation/metabolism , Inflammation/pathology , Neuropeptides/metabolism , Prosencephalon/metabolism , Prosencephalon/pathology , Acute Disease , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Chronic Disease , Escherichia coli , Galanin/metabolism , Lipopolysaccharides/toxicity , Male , Neurokinin B/metabolism , Neuropeptide Y/metabolism , Neurotensin/metabolism , Prosencephalon/drug effects , Rats , Rats, Inbred F344 , Somatostatin/metabolism , Time Factors
3.
Brain Res ; 815(1): 36-43, 1999 Jan 02.
Article in English | MEDLINE | ID: mdl-9974120

ABSTRACT

In the present study we investigated whether nitroflurbiprofen (NFP) or nitro-aspirin can reduce the inflammatory response induced by continuous infusion of lipopolysaccharide (LPS) into the fourth ventricular space of the rat's brain for 30 days. The chronic LPS infusion produced an extensive inflammation that was particularly evident in the hippocampus, subiculum and entorhinal and piriform cortices. Daily peripheral administration of NFP dose-dependently, and significantly, attenuated the brain inflammation as indicated by the decreased density and reactive state of microglial cells. Daily peripheral administration of nitro-aspirin also attenuated the brain inflammation, but to a much lesser degree than NFP. The results demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) could reduce brain inflammation and that NFP is an effective anti-inflammatory agent.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Encephalitis/drug therapy , Encephalitis/immunology , Animals , Antibodies, Monoclonal/pharmacology , Chronic Disease , Dentate Gyrus/cytology , Dentate Gyrus/immunology , Encephalitis/chemically induced , Entorhinal Cortex/cytology , Entorhinal Cortex/immunology , Immunohistochemistry , Lipopolysaccharides , Male , Microglia/immunology , Rats , Rats, Inbred F344
4.
J Neurosci ; 18(13): 5078-85, 1998 Jul 01.
Article in English | MEDLINE | ID: mdl-9634573

ABSTRACT

The neuropeptide galanin is overexpressed in the basal forebrain in Alzheimer's disease (AD). In rats, galanin inhibits evoked hippocampal acetylcholine release and impairs performance on several memory tasks, including delayed nonmatching to position (DNMTP). Galanin(1-13)-Pro2-(Ala-Leu)2-Ala-NH2 (M40), a peptidergic galanin receptor ligand, has been shown to block galanin-induced impairment on DNMTP in rats. M40 injected alone, however, does not improve DNMTP choice accuracy deficits in rats with selective cholinergic immunotoxic lesions of the basal forebrain. The present experiments used a strategy of combining M40 with an M1 cholinergic agonist in rats lesioned with the cholinergic immunotoxin 192IgG-saporin. Coadministration of intraventricular M40 with intraperitoneal 3-(3-S-n-pentyl-1,2,5-thiadiazol-4-yl)-1,2,5, 6-tetrahydro-1-methylpyridine (TZTP), an M1 agonist, improved choice accuracy significantly more than a threshold dose of TZTP alone. These results suggest that a galanin antagonist may enhance the efficacy of cholinergic treatments for the cognitive deficits of AD.


Subject(s)
Alzheimer Disease/physiopathology , Behavior, Animal/drug effects , Choice Behavior/drug effects , Galanin/pharmacology , Peptide Fragments/pharmacology , Receptors, Muscarinic/physiology , Acetylcholine/metabolism , Animals , Antibodies, Monoclonal/pharmacology , Cholinergic Agents/pharmacology , Cholinergic Fibers/drug effects , Cholinergic Fibers/physiology , Cognition/drug effects , Cognition/physiology , Disease Models, Animal , Dose-Response Relationship, Drug , Immunotoxins/pharmacology , Male , Memory/drug effects , Memory/physiology , Muscarinic Agonists/pharmacology , N-Glycosyl Hydrolases , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Muscarinic M1 , Ribosome Inactivating Proteins, Type 1 , Saporins , Thiadiazoles/pharmacology
5.
Int J Dev Neurosci ; 16(7-8): 729-35, 1998.
Article in English | MEDLINE | ID: mdl-10198820

ABSTRACT

The basal forebrain region includes a large group of cholinergic neurons within the medial septal area and nucleus basalis magnocellularis (NBM) that project to the hippocampus and throughout the neocortex, respectively. This chapter will consider the mechanisms that influence why cholinergic cells within the NBM die and discuss studies that have manipulated the features of these cells that could make them differentially vulnerable to degeneration with aging and Alzheimer's Disease (AD). This chapter will focus upon the NBM cholinergic system because this regions typically demonstrates a greater degree of cell loss with aging and AD.


Subject(s)
Acetylcholine/physiology , Cell Death/physiology , Neurons/physiology , Prosencephalon/physiology , Animals , Humans , Mitochondria/physiology , Neuritis/pathology , Neuritis/physiopathology , Prosencephalon/pathology , Substantia Innominata/pathology , Substantia Innominata/physiology
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