Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical ...trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by mitigating neuroinflammation, P2X7R blockers afford neuroprotection, increasing neuroplasticity and neuronal repair in animal models of NDDs. Finally, we reviewed previous and ongoing CTs investigating compounds directed toward targets associated with NDDs; we propose that CTs with P2X7R antagonists should be initiated. Despite the high expectations for putative P2X7Rs antagonists in various central nervous system diseases, the field is moving forward at a relatively slow pace, presumably due to the complexity of P2X7Rs. A better pharmacological approach to combat NDDs would be a dual strategy, combining P2X7R antagonism with drugs targeting a selective pathway in a given NDD.
Aluminum (Al3+) has long been related to neurotoxicity and neurological diseases. This study aims to describe the specific actions of this metal on cellular excitability and neurotransmitter release ...in primary culture of bovine chromaffin cells. Using voltage‐clamp and current‐clamp recordings with the whole‐cell configuration of the patch clamp technique, online measurement of catecholamine release, and measurements of Ca2+c with Fluo‐4‐AM, we have observed that Al3+ reduced intracellular calcium concentrations around 25% and decreased catecholamine secretion in a dose‐dependent manner, with an IC50 of 89.1 μM. Al3+ blocked calcium currents in a time‐ and concentration‐dependent manner with an IC50 of 560 μM. This blockade was irreversible since it did not recover after washout. Moreover, Al3+ produced a bigger blockade on N‐, P‐, and Q‐type calcium channels subtypes (69.5%) than on L‐type channels subtypes (50.5%). Sodium currents were also inhibited by Al3+ in a time‐ and concentration‐dependent manner, 24.3% blockade at the closest concentration to the IC50 (399 μM). This inhibition was reversible. Voltage‐dependent potassium currents were low affected by Al3+. Nonetheless, calcium/voltage‐dependent potassium currents were inhibited in a concentration‐dependent manner, with an IC50 of 447 μM. This inhibition was related to the depression of calcium influx through voltage‐dependent calcium channels subtypes coupled to BK channels. In summary, the blockade of these ionic conductance altered cellular excitability that reduced the action potentials firing and so, the neurotransmitter release and the synaptic transmission. These findings prove that aluminum has neurotoxic properties because it alters neuronal excitability by inhibiting the sodium currents responsible for the generation and propagation of impulse nerve, the potassium current responsible for the termination of action potentials, and the calcium current responsible for the neurotransmitters release.
Aluminum has neurotoxic properties because it alters neuronal excitability by inhibiting the sodium currents responsible for the generation and propagation of impulse nerve, the potassium current responsible for the termination of action potentials, and the calcium current responsible for the neurotransmitters release.
the main purpose of this study is to offer an alternative explanatory account of the functioning of cognitive techniques that is based on the principles of associative learning and highlights their ...verbal nature. The traditional accounts are questioned and analyzed in the light of the situation of psychology in the 1970s.
conceptual analysis is employed to revise the concepts of language, cognition and behavior. Several operant- and Pavlovian-based approaches to these phenomena are presented, while particular emphasis is given to Mowrer's (1954) approach and Ryle (1949) and Wittgenstein's (1953) philosophical contributions to the field.
several logical problems are found in regard to the theoretical foundations of cognitive techniques. A combination of both operant and Pavlovian paradigms based on the above-mentioned approaches is offered as an alternative explanatory account of cognitive techniques. This new approach could overcome the conceptual fragilities of the cognitive standpoint and its dependence upon constructs of dubious logical and scientific validity.
Background & Aims Although smoking is a leading risk factor for pancreatic ductal adenocarcinoma (PDAC), little is known about the mechanisms by which smoking promotes initiation or progression of ...PDAC. Methods We studied the effects of nicotine administration on pancreatic cancer development in Kras +/LSLG12Vgeo ;Elas-tTA/tetO-Cre (Ela-KRAS) mice, Kras +/LSLG12D ;Trp53+/LSLR172H;Pdx-1-Cre (KPC) mice (which express constitutively active forms of KRAS), and C57/B6 mice. Mice were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers. Pancreatic tissues were collected and analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction; cells were isolated and assayed for colony and sphere formation and gene expression. The effects of nicotine were also evaluated in primary pancreatic acinar cells isolated from wild-type, nAChR7a−/− , Trp53−/− , and Gata6−/− ; Trp53−/− mice. We also analyzed primary PDAC cells that overexpressed GATA6 from lentiviral expression vectors. Results Administration of nicotine accelerated transformation of pancreatic cells and tumor formation in Ela-KRAS and KPC mice. Nicotine induced dedifferentiation of acinar cells by activating AKT–ERK–MYC signaling; this led to inhibition of Gata6 promoter activity, loss of GATA6 protein, and subsequent loss of acinar differentiation and hyperactivation of oncogenic KRAS. Nicotine also promoted aggressiveness of established tumors as well as the epithelial–mesenchymal transition, increasing numbers of circulating cancer cells and their dissemination to the liver, compared with mice not exposed to nicotine. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells. These effects were markedly attenuated in K-Ras+/LSL-G12D ; Trp53+/LSLR172H ; Pdx-1-Cre mice given metformin. Metformin prevented nicotine-induced pancreatic carcinogenesis and tumor growth by up-regulating GATA6 and promoting differentiation toward an acinar cell program. Conclusions In mice, nicotine promotes pancreatic carcinogenesis and tumor development via down-regulation of Gata6 to induce acinar cell dedifferentiation.
In search of druggable synthetic lipids that function as potential modulators of synaptic transmission and plasticity, we synthesized sulfoglycolipid IG20, which stimulates neuritic outgrowth. Here, ...we have explored its effects on ion channels and exocytosis in bovine chromaffin cells. IG20 augmented the rate of basal catecholamine release. Such effect did not depend on Ca2+ mobilization from intracellular stores; rather, IG20‐elicited secretion entirely dependent on Ca2+ entry through L‐subtype voltage‐activated Ca2+ channels. Those channels were recruited by cell depolarization mediated by IG20 likely through its ability to enhance the recruitment of Na+ channels at more hyperpolarizing potentials. Confocal imaging with fluorescent derivative IG20‐NBD revealed its rapid incorporation and confinement into the plasmalemma, supporting the idea that IG20 effects are exerted through a plasmalemmal‐delimited mechanism. Thus, synthetic IG20 seems to mimic several physiological effects of endogenous lipids such as regulation of ion channels, Ca2+ signaling, and exocytosis. Therefore, sulfoglycolipid IG20 may become a pharmacological tool for investigating the role of the lipid environment on neuronal excitability, ion channels, neurotransmitter release, synaptic efficacy, and neuronal plasticity. It may also inspire the synthesis of druggable sulfoglycolipids aimed at increasing synaptic plasticity and efficacy in neurodegenerative diseases and traumatic brain–spinal cord injury.
The novel synthetic sulfoglycolipid IG20 mimics several physiological effects of endogenous lipids such as regulation of ion channels, Ca2+ signaling, and exocytosis. This profile may eventually drive enhanced synaptic plasticity and efficacy.
The novel synthetic sulfoglycolipid IG20 mimics several physiological effects of endogenous lipids such as regulation of ion channels, Ca2+ signaling, and exocytosis. This profile may eventually drive enhanced synaptic plasticity and efficacy.
Upon depolarization of chromaffin cells (CCs), a prompt release of catecholamines occurs. This event is triggered by a subplasmalemmal high-Ca
microdomain (HCMD) generated by Ca
entry through nearby ...voltage-activated calcium channels. HCMD is efficiently cleared by local mitochondria that avidly take up Ca
through their uniporter (MICU), then released back to the cytosol through mitochondrial Na
/Ca
exchanger (MNCX). We found that newly synthesized derivative ITH15004 facilitated the release of catecholamines triggered from high K
-depolarized bovine CCs. Such effect seemed to be due to regulation of mitochondrial Ca
circulation because: (i) FCCP-potentiated secretory responses decay was prevented by ITH15004; (ii) combination of FCCP and ITH15004 exerted additive secretion potentiation; (iii) such additive potentiation was dissipated by the MICU blocker ruthenium red (RR) or the MNCX blocker CGP37157 (CGP); (iv) combination of FCCP and ITH15004 produced both additive augmentation of cytosolic Ca
concentrations (Ca
) K
-challenged BCCs, and (v) non-inactivated Ca
transient when exposed to RR or CGP. On pharmacological grounds, data suggest that ITH15004 facilitates exocytosis by acting on mitochondria-controlled Ca
handling during K
depolarization. These observations clearly show that ITH15004 is a novel pharmacological tool to study the role of mitochondria in the regulation of the bioenergetics and exocytosis in excitable cells.
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