Journal of Neurochemistry最新文献

The serotonin transporter (SERT) belongs to the family of neurotransmitter sodium symporters (NSS), together with other neurotransmitter transporters for norepinephrine, dopamine, glycine, and GABA. The main physiological role of SERT is the retrieval of previously released serotonin from the synaptic cleft. Thereby, SERT plays an important role in regulating the extracellular serotonin concentration and maintaining serotonergic neurotransmission. This process can be influenced by molecules acting as serotonin uptake inhibitors, like paroxetine. Here, we report the development of a novel photoswitchable paroxetine derivative and its pharmacological interaction profile with SERT as a tool compound for the light-induced control of SERT. Based on the azo-extension strategy, the photoswitchable moiety was formed at the former position of the fluoro substituent in paroxetine. The resulting azo-paroxetine (9) was easily and reversibly switched between active (Z) and inactive (E) configurations and remained stable between these configurations: serotonin uptake was inhibited more than 12 times more potently by the active (Z)-configuration having a sub μM IC₅₀ value. This was supported by electrophysiological patch-clamp recordings in the whole-cell configuration and docking studies. No significant toxic impact of azo-paroxetine (9) and no off-target activity at the norepinephrine transporter (NET), human GABA transporter subtypes 1 and 3, and rat GAT1 were observed. Our results demonstrate that the activity of SERT can be reversibly manipulated by the optopharmacological agent azo-paroxetine (9). This compound can thus be applied as a tool for the selective manipulation of SERT in central or peripheral investigations, further benefiting from its low probability for compound-related off-target effects.

The axons of retinal ganglion cells (RGCs) form the optic nerve, which relays visual information to the brain. RGC degeneration is the root cause of a variety of blinding diseases linked to optic nerve damage, including glaucoma, the second leading cause of blindness worldwide. The underlying cellular mechanisms of RGC degeneration are largely unclear; yet, they have been connected to excessive production of the signalling molecule nitric oxide (NO) by nitric oxide synthase (NOS). NO activates soluble guanylate cyclase (sGC), which subsequently produces the second messenger cyclic guanosine monophosphate (cGMP). This, in turn, activates protein kinase G (PKG), which can phosphorylate downstream protein targets. To study the role of NO/cGMP/PKG signalling in RGC degeneration, we used organotypic retinal explant cultures in which the optic nerve had been severed. We assessed the activity of NOS, RGC death and survival at different times after optic nerve transection. While NOS activity was high right after optic nerve transection, significant RGC loss occurred with a 24–48-h delay. We then treated retinal explants with inhibitors selectively targeting either NOS, sGC, PKG, or Kv1.3 and Kv1.6 voltage-gated potassium channels. While all four treatments reduced RGC death, the PKG inhibitor CN238 and the Kv-channel blocker Margatoxin (MrgX) showed the most pronounced rescue effects. Our results confirm an involvement of NO/cGMP/PKG signalling in RGC degeneration, highlight the potential of PKG and Kv1-channel targeting drugs for treatment development, and further suggest organotypic retinal explant cultures as a useful model for investigations into optic nerve damage.

Over the past two decades, a growing number of studies have been conducted on the role of bidirectional communication through the gut–brain axis in the development of neurodegenerative diseases. These studies were driven by the curious fact that all of these diseases present varying degrees of intestinal involvement included in their wide range of symptoms. A population of cells belonging to the ENS, called enteric glial cells (EGCs), appears to actively participate in this communication between the intestine and the brain, but acting in a dualistic manner, sometimes in reactive gliosis releasing inflammatory mediators, sometimes promoting homeostasis and resilience in the face of inflammatory injuries. To date, the intracellular mechanisms that define the transcriptional profile expressed in EGCs in each situation have not yet been elucidated. This review proposes a discussion on: (1) the complex role of distinct phenotypes of enteric glial cells involved in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS); and (2) innovative strategies such as IDO/TDO inhibitors, Brazil nuts, caffeic acid, polyphenols, among others, that act on EGCs and have the potential to treat neurodegenerative diseases.

Touchscreen-based methodologies have enabled significant advancements in cognitive neuroscience by providing standardized, translationally relevant assessments of advanced cognitive functions in rodent models. This special issue highlights the potential of these systems to bridge animal and human research, providing insights into the neurochemical and biological mechanisms underlying cognition. The included studies explore diverse applications, from understanding the cognitive impacts of chronic stress and maternal immune activation to evaluating the effectiveness of novel therapeutics and assessing cross-species cognitive testing approaches that enhance translational relevance. By combining touchscreen technologies with cutting-edge approaches like electrophysiology and open science databases, these contributions underscore the critical role of automated systems in advancing translational research. Together, they lay the foundation for novel therapeutic strategies to address cognitive deficits in brain disorders.

RETRACTION: O. Ghribi, M. M. Herman, N. K. Spaulding, and J. Savory, “Lithium Inhibits Aluminum-Induced Apoptosis in Rabbit Hippocampus, by Preventing Cytochrome c Translocation, Bcl-2 Decrease, Bax Elevation and Caspase-3 Activation,” Journal of Neurochemistry 82, no. 1 (2002): 137-145, https://doi.org/10.1046/j.1471-4159.2002.00957.x.

The above article, published online on 25 June 2002 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Andrew Lawrence; the International Society for Neurochemistry; and John Wiley & Sons Ltd. A third party notified the journal about concerns of image duplication in this article. Further investigation by the publisher and the journal confirmed that images in Figure 2b had been duplicated and rotated, bands in Figure 3 had been duplicated and rotated, an image had been duplicated between Figure 4b(i) and Figure 5a, an actin band had been duplicated between Figure 2a and Figure 3, and band in Figure 1 had been potentially duplicated and resized. Some authors could not be reached, and the remaining authors otherwise did not respond to inquiries by the journal and publisher. The retraction has been agreed to because the evidence of image duplication, rotation, and resizing fundamentally compromises the conclusions presented in the article and, due to the lack of original data, the conclusions cannot be verified. The authors did not respond to our notice regarding the retraction.

Neuromodulation encompasses different processes that regulate neuronal and network function. Classical neuromodulators originating from long-range nuclei, such as acetylcholine, norepinephrine, or dopamine, act with a slower time course and wider spatial range than fast synaptic transmission and action potential firing. Accumulating evidence in vivo indicates that astrocytes, which are known to actively participate in synaptic function at tripartite synapses, are also involved in neuromodulatory processes. The present article reviews recent findings obtained in vivo indicating that astrocytes express receptors for neuromodulators that elevate their internal calcium and stimulate the release of gliotransmitters, which regulate synaptic and network function, and hence mediate, at least partially, the effects of neuromodulators. In addition, we propose that astrocytes act in local support of neuromodulators by spatially and temporally integrating neuronal and neuromodulatory signals to regulate neural network function. The presence of astrocyte-neuron hysteresis loops suggests astrocyte–neuron interaction at tripartite synapses scales up to astrocyte–neuronal networks that modulate neural network function. We finally propose that astrocytes sense the environmental conditions, including neuromodulators and network function states, and provide homeostatic control that maximizes the dynamic range of neural network activity. In summary, we propose that astrocytes are critical in mediating the effects of neuromodulators, and they also act as neuromodulators to provide neural network homeostasis thus optimizing information processing in the brain. Hence, astrocytes sense ongoing neuronal activity along with neuromodulators and, acting as neuromodulators, inform the neurons about the state of the internal system and the external world.

Chronic neuropathic pain is a debilitating condition that presents a significant therapeutic challenge. Unlike nociceptive pain, neuropathic pain is predominantly driven by glutamate NMDA receptors (NMDARs) and/or Ca²⁺-permeable AMPA receptors (CP-AMPARs) at synapses between primary afferent nerves and excitatory neurons in the spinal dorsal horn. The α2δ-1 protein, encoded by Cacna2d1 and historically recognized as a subunit of voltage-activated Ca²⁺ channels, is the primary target of gabapentinoids, such as gabapentin and pregabalin, which are widely prescribed for neuropathic pain and epilepsy. However, gabapentinoids have minimal effects on Ca²⁺ channel activity. Recent studies reveal that α2δ-1 plays a pivotal role in amplifying nociceptive input to the spinal cord in neuropathic pain. This action is mediated through its dynamic physical interactions with phosphorylated NMDARs and GluA1/GluA2 subunits via its intrinsically disordered C-terminal region. α2δ-1 not only promotes synaptic trafficking of NMDARs but also disrupts heteromeric assembly of GluA1/GluA2 subunits in the spinal dorsal horn. The central function of α2δ-1 is to elevate intracellular Ca²⁺ concentrations at both presynaptic and postsynaptic sites, augmenting nociceptive transmission. Consequently, α2δ-1 serves as a dual regulator coordinating synaptic expression of NMDARs and GluA1 homomeric CP-AMPARs, a function that underlies the therapeutic actions of gabapentinoids. By inhibiting α2δ-1, gabapentinoids reduce the hyperactivity of synaptic α2δ-1-bound NMDARs and CP-AMPARs, thereby dampening the excessive excitatory synaptic transmission characteristic of neuropathic pain. These newly identified roles of α2δ-1 in orchestrating glutamatergic synaptic plasticity suggest that gabapentinoids could be repurposed for treating other neurological disorders involving dysregulated synaptic NMDARs and CP-AMPARs.