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At least 109 records · Page 6Linked to original sources
PubMed1994

Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease.

Recent evidence indicates that apolipoprotein E (ApoE) plays a central role in the hippocampal response to injury. The co-ordinated expression of ApoE and its receptor, the ApoE/ApoB [low density lipoprotein (LDL)] receptor, appears to regulate the transport of cholesterol and phospholipids during the early and intermediate phases of the reinnervation process. During dendritic remodeling and synaptogenesis, neurons progressively repress the synthesis of cholesterol in favor of cholesterol internalization through the ApoE/LDL receptor pathway. The discovery that the epsilon 4 allele is strongly linked to both sporadic and familial late-onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid-transport system associated with compensatory sprouting and synaptic remodeling could be central to the AD process. The role of ApoE in the CNS is particularly important in relation to the function of the cholinergic system, which relies to a certain extent on the integrity of phospholipid homeostasis in neurons. Recent evidence suggests that the epsilon 4 allele has a direct impact on cholinergic function in AD.

Alzheimer Disease↗
PubMedDate not supplied

Lead-impaired neurodevelopment. Mechanisms and threshold values in the rodent.

Mechanisms underlying the cognitive deficits arising from chronic low level lead exposure are viewed as a consequence of impaired neurodevelopmental events. These events are exemplified within the cerebellum which is formed completely after birth and, therefore, encompasses all major epochs of development. Further, the unique pharmacokinetic distribution of juvenile blood lead levels is developmentally regulated and can be correlated to the periods of impaired structuring and threshold values indicating no-effect levels established. Here, the endpoint value is related to lead-induced dysfunctioning of a morphoregulator--the neural cell adhesion molecule (NCAM). During final synaptic structuring its normal developmental sequence is perturbed when blood lead levels exceed 20 micrograms/dl. These events are similar, and compared to, those seen in the cerebellum of the staggerer mouse mutant (sg/sg) where the selection of circuits to be preserved from those transiently overproduced during development is impaired.

Animals↗
PubMed2026

The Thyroid-Brain Network: Exploring Inflammation, Immune Mechanisms and Common Triggers in Thyroid-Related Neurological Dysfunction.

Autoimmune thyroid diseases (AITD), including Hashimoto's thyroiditis and Graves' disease, represent the most prevalent endocrine disorders worldwide, affecting hundreds of millions with profound but often under recognized neurological consequences. There are emerging lines of evidence establishing inflammation and immunity as the critical missing link connecting peripheral thyroid dysfunction to central nervous system manifestations. Thyroid hormones function as essential neuromodulators governing neurodevelopment, synaptic plasticity, and cognitive processing through integrated genomic and non-genomic mechanisms, with region-specific cerebral metabolic disturbances correlating with distinct neuropsychiatric symptoms. The immunological perspective reveals that AITD propagates neuroinflammation through convergent pathways: molecular mimicry enabling cross-reactivity between thyroid and neural antigens, cytokine-mediated disruption of neurotransmitter metabolism, HMGB1-driven glial activation, and blood-brain barrier compromise facilitating immune cell infiltration. The thyroid-gut-microbiota axis emerges as a critical mediator wherein dysbiosis perpetuates both thyroid autoimmunity and neuroinflammation through impaired serotonin precursor availability and increased intestinal permeability. Mitochondrial dysfunction represents an energetic common denominator, as thyroid hormone dysregulation directly impairs oxidative phosphorylation, producing region-specific cerebral metabolic disturbances. Simultaneous compromise of monoamine systems, cholinergic signaling abnormalities, and glutamate excitotoxicity creates a particularly toxic neurochemical state in untreated thyroid dysfunction. Common triggers such as psychological stress, gut dysbiosis, and mitochondrial impairment may activate interconnected pathways that simultaneously compromise thyroid and brain function, revealing that these disorders share fundamental mechanistic origins. These insights have been discussed in the current review to enhance the understanding of thyroid-brain function, the core mechanisms and consequences of functional deficits.

Journal Article↗
PubMed1994

Ketamine prevents ECS-induced synaptic enhancement in rat hippocampus.

Electrical induction of seizure activity profoundly impairs hippocampal long-term potentiation (LTP) in rats. A similar effect may account for the memory dysfunction observed after electroconvulsive stimulation in humans and other species. The co-administration of ketamine with the induction of electroconvulsive seizures (ECS) was evaluated as a possible method for reducing the impact of ECS on hippocampal synaptic plasticity in rats. Electrophysiological studies in vivo showed that both the enhancement of the EPSP slope and the subsequent reduction of experimentally induced LTP in the dentate gyrus by repeated, spaced ECS were significantly attenuated by ketamine anaesthesia. The findings suggest that ketamine may protect against ECS-induced memory impairment and thus prove useful in reducing the transient cognitive impairment following electroconvulsive therapy (ECT).

Animals↗
PubMed1994

Cholinergic denervation of the rat hippocampus by 192-IgG-saporin: electrophysiological evidence.

The consequences of intracerebroventricular injection of the toxin 192-IgG-saporin on the electrophysiological properties of CA1 pyramidal cells were investigated using intracellular recordings in the in vitro hippocampal slice preparation. We present the first electrophysiological evidence of a dysfunction of hippocampal cholinergic afferents following injection of 192-IgG-saporin. The synaptic events mediated by acetylcholine were altered in such animals: the slow cholinergic excitatory postsynaptic potentials as well as the cholinergic activation of GABAergic interneurones were dramatically depressed or even absent; the amplitude and duration of the afterhyperpolarization following a burst of spikes were increased, while other neuronal properties were not modified. These specific alterations suggest that the toxin 192-IgG-saporin is a specific tool for the experimental study of cholinergic denervation in the hippocampus.

Animals↗
PubMed2026

CNNM2 in schizophrenia: multilevel evidence of genetic susceptibility, magnesium homeostasis, neurodevelopment and cognitive dysfunction.

Schizophrenia (SCZ) is a common psychiatric disorder with a complex, genetically and environmentally influenced etiology, but the specific pathogenesis remains unclear. In recent years, the SCZ susceptibility gene CNNM2 (encoding cyclin M2) located at the 10q24.32-33 locus has received widespread attention. The well-validated SCZ risk interval 10q24.32-33 harbors two independent risk variants: rs11191580 in NT5C2 (significantly associated with CNNM2 mRNA and protein levels) and rs7914558 in CNNM2. Results from functional genomic analyses indicate that lower CNNM2 expression is significantly associated with SCZ. Imaging genetics studies have demonstrated that carriers of risk alleles of CNNM2 SNPs exhibit alterations in brain structure. Animal model studies have revealed that Cnnm2 downregulation in mice leads to impairments in sensorimotor gating and cognitive function. As an Mg2+ transporter, CNNM2 primarily maintains systemic Mg2+ homeostasis. According to clinical studies, a proportion of patients with SCZ exhibit reduced Mg2+ concentrations in plasma and cerebrospinal fluid. CNNM2 dysfunction may contribute to the pathology of SCZ by disrupting Mg2+ homeostasis, thereby affecting neurodevelopment and synaptic plasticity. A systematic consolidation of current evidence supporting the involvement of CNNM2 in SCZ pathogenesis provides a direction for further investigation of the pathological mechanisms underlying this disease, and for identification of novel targets for clinical intervention..

Schizophrenia↗
PubMed1987

Reduced uptake and release of 5-hydroxytryptamine and taurine in the cerebral cortex of epileptic El mice.

Inbred mutant El mice are highly susceptible to convulsive seizures upon 'throwing' stimulation, and the inhibition of 5-hydroxytryptamine (5-HT) and taurine activities appears to be involved in the El mouse seizures. Uptake and release of [3H]5-HT and [3H]taurine into and from cerebral neurocortical slices using a superfusion system were investigated in both non-stimulated and stimulated El mice [El(-), El(+)] and in ddY mice, which do not have a convulsive disposition. Release was defined as 40 mM K+-stimulated release. 5-HT and taurine uptake in El(+) was lower than El(-) but no difference in either uptake was found between ddY and El(-). Release of 5-HT and taurine in El(-) was higher than in ddY whereas their release in El(+) was lower than in El(-). The taurine level in the cerebral neocortex of El(-) and El(+) was higher than in ddY. These results suggest that the synaptic function of the 5-HT and taurine containing neurons is suppressed and that dysfunction of these inhibitory neurons is involved in the seizure susceptibility in the El mice.

Animals↗
PubMed2025

Protective effects of liver-derived apolipoprotein A1 against heat stress-induced hypothalamic lipid metabolism and blood-brain barrier integrity.

Heat stress (HS), a prevalent occupational and environmental hazard, has increasingly been recognized as a major contributor to multiple physiological disorders. The hypothalamus, a key regulator of thermoregulation and endocrine signaling, is especially susceptible to metabolic and inflammatory disturbances induced by HS. This study investigates the interplay among lipid metabolism, blood-brain barrier (BBB) integrity, and neuroinflammation in the hypothalamus under HS conditions, with a specific focus on apolipoprotein A1 (APOA1) as a potential protective factor. To achieve this, we integrated proteomic and lipidomic analyses with experimental validation in porcine and murine models. Proteomic analysis identified 266 differentially expressed proteins (DEPs) in the hypothalamus following HS, with significant enrichment in lipid metabolism pathways-especially glycerophospholipid (GP) metabolism-in which APOA1 displayed a marked increase. Lipidomic profiling further revealed HS-induced disruptions in phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) metabolism. Additionally, blood-brain barrier integrity was compromised, as evidenced by increased perivascular IgG extravasation, reduced pericyte coverage, and decreased expression of tight junction proteins ZO-1 and Occludin. HS also triggered pronounced neuroinflammation, characterized by elevated levels of iNOS, GFAP, and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Notably, administration of D-4F, an APOA1 mimetic peptide, alleviated blood-brain barrier damage, reduced neuroinflammation, and preserved synaptic integrity, thereby suggesting a neuroprotective role for APOA1 in HS-induced hypothalamic dysfunction. These findings underscore the critical role of lipid metabolism in maintaining hypothalamic homeostasis under HS conditions and position APOA1 as a key regulator with potential therapeutic implications for mitigating HS-related neuroinflammatory and metabolic disturbances.

Blood-Brain Barrier↗
PubMed1987

Speculations on disease states induced by excitatory amino acids.

There is much current interest in excitatory amino acids and their receptors because of their postulated involvement in several disorders of the nervous system. They function as neurotransmitters, but can act as neurotoxins in some situations. They have been implicated in the pathogenesis of cerebral hypoxic/ischemic and hypoglycemic damage, in epilepsy, in some degenerative diseases, and in some forms of neurotoxin-induced cerebral dysfunction. These diseases may reflect abnormality in a system which has evolved to provide synaptic plasticity essential for learning and memory. The purpose of this paper is to explore the ramifications of such a hypothesis.

Amino Acids↗
PubMed1992

A preliminary observation on auto-cholinergic synapse dysfunction in patients with different types of epilepsy.

Serum anti-acetylcholine receptor antibodies (A AchR Ab) and anti-synaptic premembrane antibodies (A PrM Ab) were measured in 21 patients with absence epilepsy, 21 cases with benign childhood epilepsy with centro-temporal spikes (BCECTs) and 13 cases with atypical epilepsy. Respectively, in five (23.8%), eleven (51.2%) and eight (66.7%) of the above mentioned groups of patients both A AchR Ab and A PrM Ab were found.

Adolescent↗
PubMed1989

[Intrapenile neurotransmission. Physiologic data and practical consequences].

This paper reviews the intrapenile control of erection and the principal pathophysiological and therapeutic implications (especially intracavernous injections) of these physiological data. The regulation of flaccidity is fairly well known. This principally results from a continuous adrenergic discharge responsible, via activation of the alpha receptors, for tonic contraction of the smooth muscle fibres (SMF) of the corpora cavernosa (CC), preventing blood from entering the spaces of the CC. The complementary role of serotonin, histamine, prostaglandins (PG) F1 and F2 alpha and neuropeptide Y is still unclear. The regulation of erection is less well understood. The principal phenomenon is probably inhibition of the anti-erectile alpha adrenergic tone, allowing relaxation of the SMF and congestion of the areolae of the CC, influx of arterial blood and occlusion of the venous exits. However, an additional relaxing nervous stimulation may also be required. The modulation of anti-erectile adrenergic activity could be the result of Vasoactive-Intestinal-Polypeptide which, however, is unable to induce complete erection on its own, and/or PGE1. Acetylcholine, whose role is still unclear, stimulation of beta adrenergic receptors and presynaptic alpha-2 receptors, histamine, a relaxant factor of endothelial origin and possibly other neurotransmitters as yet unidentified, may also be involved.

Alprostadil↗
PubMed1995

Clinical use of metaiodobenzylguanidine imaging in cardiology.

Cardiac function is predominantly regulated by autonomic innervation. Many heart diseases involve alterations of cardiac adrenergic neurotransmission. In patients with cardiomyopathies, numerous therapeutic agents act directly or indirectly on cardiac adrenergic disorders. Metaiodobenzylguanidine (MIBG) imaging can provide in vivo information on one of the main components of adrenergic nerve function, i.e. the norepinephrine reuptake and storage system. Diminished MIBG uptake has been reported in patients with congestive heart failure, indicating an impaired norepinephrine reuptake and storage system. In patients with dilated cardiomyopathy (either idiopathic or ischemic), this alteration has been linked to the severity of the disease, evaluated on the basis of clinical or hemodynamic parameters. Moreover, MIBG imaging has been reported in such patients to be a potent prognostic marker in comparison with other recognized indices. After myocardial infarction, the decrease in MIBG uptake was transient in some patients and was suggested to be a viability indicator. Diminished MIBG uptake in ischemic patients was linked to the occurrence of ventricular arrhythmias. In patients with primary hypertrophic cardiomyopathy, decreased cardiac MIBG uptake has also been related to the clinical indices of severity. In patients suffering from various arrhythmias such as idiopathic ventricular arrhythmias, arrhythmogenic right ventricular cardiomyopathy or a long-QT syndrome, MIBG imaging has evidenced regional abnormalities of adrenergic nerve function and has provided new insights into the pathophysiological mechanisms of such disorders. Finally, MIBG scintigraphy may permit the evaluation of anthracyclin cardiotoxicity. Thus, MIBG imaging appears to be a promising tool for the cardiologist.

3-Iodobenzylguanidine↗
PubMed1997

Trans-synaptic stimulation of cortical acetylcholine and enhancement of attentional functions: a rational approach for the development of cognition enhancers.

Activation and restoration of cholinergic function remain major foci in the development of pharmacological approaches toward the treatment of cognitive dysfunctions associated with aging and dementia. Our research has been guided by the hypothesis that (re)activation of cortical cholinergic inputs is achieved as a result of trans-synaptic disinhibition of basal forebrain cholinergic neurons. This approach depends on the ability of benzodiazepine receptor (BZR) inverse agonists to reduce the potency of GABA to block neuronal excitation. BZR inverse agonists were found to augment cortical ACh efflux through interaction with cognition-associated activation of this system. Cortical cholinergic inputs have been implicated in the processing of behaviorally significant stimuli, i.e., attentional functions. Using a recently developed and validated task for the measurement of sustained attention, or vigilance, administration of BZR inverse agonists were found to selectively increase the number of false alarms in intact animals. However, in animals with a 50-70%, but not > 90%, loss of the cortical cholinergic inputs, treatment with BZR inverse agonists alleviated the lesion-induced impairment in sustained attention and enhanced activated cortical ACh efflux. A rational development of cognitive enhancers will benefit from experiments in which cognitive and neuropharmacological variables are assessed simultaneously, thus allowing the analysis of interactions between cognition-associated neuronal activity and the neuronal and cognitive effects of putative cognition enhancers.

Acetylcholine↗
PubMed1976

Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease.

Golgi and electron microscope studies of cortical neurons in several lysosomal storage diseases were carried out to elucidate structural features of the large neural processes (meganeurites) that develop as storage sites for accumulated undigestible substrates. Meganeurites occur preferentially in pyramidal neurons wherein they develop between the base of the perikaryon and the initial portion of the axon. They frequently give rise to secondary neurites which bear filopodium-like processes. Meganeurites may possess spines some of which are contacted by presynaptic processes containing synaptic vesicles. The extent of meganeurite development is related to the onset, severity and clinical course of neuronal storage disease. Extensive development of bizarre and pleomorphic meganeurites occurs in classical Tay-Sachs disease (infantile GM2-gangliosidosis, B variant), whereas a smaller proportion of neurons exhibits meganeurites in juvenile GM2-hangliosidosis and Hurler's disease. Meganeurites with spines and spine synapses were prominent in GM2-gangliosidosis, AB variant. It is proposed that meganeurites and meganeurite synapses contribute to the onset and progression of neuronal dysfunction in storage diseases by altering electrical properties of the neuron and modifying integrative operations of somadendritic synaptic inputs.

Adolescent↗
PubMed1983

Clinical studies of monoamine receptors in the affective disorders and receptor changes with antidepressant treatment.

Pre-clinical and clinical studies suggest that the responsiveness of monoamine and cholinergic receptors may be altered in the affective disorders and that antidepressants may modify the sensitivity of these receptors. The growth hormone response to clonidine is reduced in depressed patients compared to controls according to several independent studies, suggesting that post-synaptic alpha 2-adrenergic receptors may be less responsive in depressed patients. The cortisol response to clonidine is enhanced in depressed patients compared to controls in our study raising the possibility that cortisol hypersecretion in depressed patients may be related to noradrenergic dysfunction. The hypotensive response to clonidine is blunted in patients on chronic antidepressant treatment with either clorgyline or desipramine suggesting that pre-synaptic alpha 2-adrenergic receptors may subsensitize with chronic antidepressant treatment. The prolactin increase in response to fenfluramine is less in depressed patients compared to controls suggesting decreased functional activity of the serotonergic system in depression. Platelet alpha 2-adrenergic receptor number as measured by tritiated dihydroergocriptine (3H-DHE) binding is increased in depressed patients compared to controls, while cyclic 3'-5' adenosine monophosphate (cAMP) production in response to prostaglandin E1 (PGE1) and norepinephrine (NE) inhibition of PGE1-stimulated cAMP production are reduced in the platelets of depressed patients. Thus, it is not clear that increased 3H-DHE binding reflects increased functional responsiveness and might in fact be compensatory to decreases in functional responses of alpha 2-adrenergic receptors.

Clonidine↗
PubMed1995

Lead inhibits Ca(2+)-stimulated nitric oxide synthase activity from rat cerebellum.

Pb2+ is reported to cause cognitive dysfunctions in children and to inhibit long-term potentiation (LTP), a model form of synaptic plasticity that involves nitric oxide (NO). Since Pb2+ interacts with Ca(2+)-calmodulin, and brain nitric oxide synthase (NOS) is Ca(2+)-calmodulin regulated, we examined the effects of Pb2+ on NOS activity prepared from rat cerebellum. NOS required NADPH and was inhibited by monomethylarginine. Full NOS activity required 0.6 microM free Ca2+ and was inhibited 50% by 17 nM and 100% by 80 nM free Pb2+. NOS inhibition by Pb2+ was reversible by increasing free Ca2+ concentrations. Evaluation of other divalent cations resulted in the following ranked order of potencies: Cu2+ > Pb2+ >> Zn2+; Fe2+, Ba2+, Mg2+, Mn2+, and Sr2+ were ineffective. These results suggest that Pb2+ inhibition of brain NOS activity may account for some of the effects of Pb2+ on the CNS.

Animals↗