-
Frontiers in Neurology 2024Traumatic brain injury (TBI), a leading cause of high morbidity and mortality, represents a significant global public health challenge. Currently, no effective treatment...
BACKGROUND AND AIM
Traumatic brain injury (TBI), a leading cause of high morbidity and mortality, represents a significant global public health challenge. Currently, no effective treatment for TBI exists. Curcumin, an active compound extracted from the root of , has demonstrated neuroprotective properties both and . Notably, it has shown potential in reducing oxidative stress and inflammation and enhancing redox balance. This paper conducts a systematic review and meta-analysis to explore curcumin's role in TBI animal models extensively. The findings offer valuable insights for future human clinical trials evaluating curcumin as a therapeutic supplement or nutraceutical in TBI management.
METHODS
Comprehensive literature searches were conducted across MEDLINE, Embase, Cochrane, Web of Science, and Google Scholar databases. These searches aimed to identify relevant manuscripts in all languages, utilizing the keywords "curcumin" and "traumatic brain injury."
RESULTS
The final quantitative analysis included 18 eligible articles corresponding to animal studies. The analysis revealed that curcumin significantly reduced inflammatory cytokines, including IL-1β ( = 0.000), IL-6 ( = 0.002), and TNF-α ( = 0.000), across various concentrations, time points, and administration routes. Additionally, curcumin markedly enhanced the activity of oxidative stress markers such as SOD ( = 0.000), Sir2 ( = 0.000), GPx ( = 0.000), and Nrf2 ( = 0.000), while reducing MDA ( = 0.000), 4-HNE ( = 0.001), and oxyprotein levels ( = 0.024). Furthermore, curcumin improved cerebral edema ( = 0.000) and upregulated neuroprotective factors like synapsin I ( = 0.019), BDNF ( = 0.000), and CREB ( = 0.000), without reducing mNSS ( = 0.144). About autophagy and apoptosis, curcumin increased the activity of Beclin-1 ( = 0.000) and Bcl-2 ( = 0.000), while decreasing caspase-3 ( = 0.000), the apoptosis index ( = 0.000), and P62 ( = 0.002).
CONCLUSION
Curcumin supplementation positively affects traumatic brain injury (TBI) by alleviating oxidative stress and inflammatory responses and promoting neuroprotection. It holds potential as a therapeutic agent for human TBI. However, this conclusion necessitates further substantiation through high-quality literature and additional randomized controlled trials (RCTs).
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/. The registration number of PROSPERO: CRD42023452685.
PubMed: 38798711
DOI: 10.3389/fneur.2024.1380353 -
Biomolecules May 2024Excitotoxicity is a common pathological process in neurological diseases caused by excess glutamate. The purpose of this study was to evaluate the effect of gypenoside...
Excitotoxicity is a common pathological process in neurological diseases caused by excess glutamate. The purpose of this study was to evaluate the effect of gypenoside XVII (GP-17), a gypenoside monomer, on the glutamatergic system. In vitro, in rat cortical nerve terminals (synaptosomes), GP-17 dose-dependently decreased glutamate release with an IC value of 16 μM. The removal of extracellular Ca or blockade of N-and P/Q-type Ca channels and protein kinase A (PKA) abolished the inhibitory effect of GP-17 on glutamate release from cortical synaptosomes. GP-17 also significantly reduced the phosphorylation of PKA, SNAP-25, and synapsin I in cortical synaptosomes. In an in vivo rat model of glutamate excitotoxicity induced by kainic acid (KA), GP-17 pretreatment significantly prevented seizures and rescued neuronal cell injury and glutamate elevation in the cortex. GP-17 pretreatment decreased the expression levels of sodium-coupled neutral amino acid transporter 1, glutamate synthesis enzyme glutaminase and vesicular glutamate transporter 1 but increased the expression level of glutamate metabolism enzyme glutamate dehydrogenase in the cortex of KA-treated rats. In addition, the KA-induced alterations in the N-methyl-D-aspartate receptor subunits GluN2A and GluN2B in the cortex were prevented by GP-17 pretreatment. GP-17 also prevented the KA-induced decrease in cerebral blood flow and arginase II expression. These results suggest that (i) GP-17, through the suppression of N- and P/Q-type Ca channels and consequent PKA-mediated SNAP-25 and synapsin I phosphorylation, reduces glutamate exocytosis from cortical synaptosomes; and (ii) GP-17 has a neuroprotective effect on KA-induced glutamate excitotoxicity in rats through regulating synaptic glutamate release and cerebral blood flow.
Topics: Animals; Glutamic Acid; Rats; Male; Gynostemma; Cyclic AMP-Dependent Protein Kinases; Rats, Sprague-Dawley; Synaptosomes; Neuroprotective Agents; Kainic Acid; Seizures; Synapses; Synaptosomal-Associated Protein 25; Synapsins; Phosphorylation; Calcium; Plant Extracts
PubMed: 38785996
DOI: 10.3390/biom14050589 -
International Journal of Molecular... Apr 2024Adipose-derived mesenchymal stem cells (ASCs) are adult multipotent stem cells, able to differentiate toward neural elements other than cells of mesodermal lineage. The...
Adipose-derived mesenchymal stem cells (ASCs) are adult multipotent stem cells, able to differentiate toward neural elements other than cells of mesodermal lineage. The aim of this research was to test ASC neural differentiation using melatonin combined with conditioned media (CM) from glial cells. Isolated from the lipoaspirate of healthy donors, ASCs were expanded in a basal growth medium before undergoing neural differentiation procedures. For this purpose, CM obtained from olfactory ensheathing cells and from Schwann cells were used. In some samples, 1 µM of melatonin was added. After 1 and 7 days of culture, cells were studied using immunocytochemistry and flow cytometry to evaluate neural marker expression (Nestin, MAP2, Synapsin I, GFAP) under different conditions. The results confirmed that a successful neural differentiation was achieved by glial CM, whereas the addition of melatonin alone did not induce appreciable changes. When melatonin was combined with CM, ASC neural differentiation was enhanced, as demonstrated by a further improvement of neuronal marker expression, whereas glial differentiation was attenuated. A dynamic modulation was also observed, testing the expression of melatonin receptors. In conclusion, our data suggest that melatonin's neurogenic differentiation ability can be usefully exploited to obtain neuronal-like differentiated ASCs for potential therapeutic strategies.
Topics: Melatonin; Mesenchymal Stem Cells; Humans; Cell Differentiation; Cells, Cultured; Adipose Tissue; Neurons; Culture Media, Conditioned; Schwann Cells; Neurogenesis; Adult; Nestin; Glial Fibrillary Acidic Protein; Neuroglia; Synapsins
PubMed: 38732109
DOI: 10.3390/ijms25094891 -
ELife May 2024The cytosolic proteins synucleins and synapsins are thought to play cooperative roles in regulating synaptic vesicle (SV) recycling, but mechanistic insight is lacking....
The cytosolic proteins synucleins and synapsins are thought to play cooperative roles in regulating synaptic vesicle (SV) recycling, but mechanistic insight is lacking. Here, we identify the synapsin E-domain as an essential functional binding-partner of α-synuclein (α-syn). Synapsin E-domain allows α-syn functionality, binds to α-syn, and is necessary and sufficient for enabling effects of α-syn at synapses of cultured mouse hippocampal neurons. Together with previous studies implicating the E-domain in clustering SVs, our experiments advocate a cooperative role for these two proteins in maintaining physiologic SV clusters.
Topics: alpha-Synuclein; Animals; Synapsins; Mice; Neurons; Hippocampus; Protein Binding; Synaptic Vesicles; Protein Domains; Cells, Cultured; Humans; Synapses
PubMed: 38713200
DOI: 10.7554/eLife.89687 -
Neurotherapeutics : the Journal of the... May 2024Hemorrhage-induced injury of the corticospinal tract (CST) in the internal capsule (IC) causes severe neurological dysfunction in both human patients and rodent models...
Hemorrhage-induced injury of the corticospinal tract (CST) in the internal capsule (IC) causes severe neurological dysfunction in both human patients and rodent models of intracerebral hemorrhage (ICH). A nuclear receptor Nurr1 (NR4A2) is known to exert anti-inflammatory and neuroprotective effects in several neurological disorders. Previously we showed that Nurr1 ligands prevented CST injury and alleviated neurological deficits after ICH in mice. To prove direct effect of Nurr1 on CST integrity, we examined the effect of Nurr1 overexpression in neurons of the primary motor cortex on pathological consequences of ICH in mice. ICH was induced by intrastriatal injection of collagenase type VII, where hematoma invaded into IC. Neuron-specific overexpression of Nurr1 was induced by microinjection of synapsin I promoter-driven adeno-associated virus (AAV) vector into the primary motor cortex. Nurr1 overexpression significantly alleviated motor dysfunction but showed only modest effect on sensorimotor dysfunction after ICH. Nurr1 overexpression also preserved axonal structures in IC, while having no effect on hematoma-associated inflammatory events, oxidative stress, and neuronal death in the striatum after ICH. Immunostaining revealed that Nurr1 overexpression increased the expression of Ret tyrosine kinase and phosphorylation of Akt and ERK1/2 in neurons in the motor cortex. Moreover, administration of Nurr1 ligands 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane or amodiaquine increased phosphorylation levels of Akt and ERK1/2 as well as expression of glial cell line-derived neurotrophic factor and Ret genes in the cerebral cortex. These results suggest that the therapeutic effect of Nurr1 on striatal ICH is attributable to the preservation of CST by acting on cortical neurons.
PubMed: 38704311
DOI: 10.1016/j.neurot.2024.e00370 -
Cell Death & Disease Apr 2024Abnormal intraneuronal accumulation of soluble and insoluble α-synuclein (α-Syn) is one of the main pathological hallmarks of synucleinopathies, such as Parkinson's...
Abnormal intraneuronal accumulation of soluble and insoluble α-synuclein (α-Syn) is one of the main pathological hallmarks of synucleinopathies, such as Parkinson's disease (PD). It has been well documented that the reversible liquid-liquid phase separation of α-Syn can modulate synaptic vesicle condensates at the presynaptic terminals. However, α-Syn can also form liquid-like droplets that may convert into amyloid-enriched hydrogels or fibrillar polymorphs under stressful conditions. To advance our understanding on the mechanisms underlying α-Syn phase transition, we employed a series of unbiased proteomic analyses and found that actin and actin regulators are part of the α-Syn interactome. We focused on Neural Wiskott-Aldrich syndrome protein (N-WASP) because of its association with a rare early-onset familial form of PD. In cultured cells, we demonstrate that N-WASP undergoes phase separation and can be recruited to synapsin 1 liquid-like droplets, whereas it is excluded from α-Syn/synapsin 1 condensates. Consistently, we provide evidence that wsp-1/WASL loss of function alters the number and dynamics of α-Syn inclusions in the nematode Caenorhabditis elegans. Together, our findings indicate that N-WASP expression may create permissive conditions that promote α-Syn condensates and their potentially deleterious conversion into toxic species.
Topics: alpha-Synuclein; Animals; Humans; Caenorhabditis elegans; Wiskott-Aldrich Syndrome Protein, Neuronal; Actins; Parkinson Disease; Synapsins; Caenorhabditis elegans Proteins
PubMed: 38693139
DOI: 10.1038/s41419-024-06686-7 -
Brain Research Bulletin Jun 2024In clinical trials for Alzheimer's disease (AD), hydromethylthionine mesylate (HMTM) showed reduced efficacy when administered as an add-on to symptomatic treatments,...
In clinical trials for Alzheimer's disease (AD), hydromethylthionine mesylate (HMTM) showed reduced efficacy when administered as an add-on to symptomatic treatments, while it produced a significant improvement of cognitive function when taken as monotherapy. Interference of cholinesterase inhibition with HMTM was observed also in a tau transgenic mouse model, where rivastigmine reduced the pharmacological activity of HMTM at multiple brain levels including hippocampal acetylcholine release, synaptosomal glutamate release and mitochondrial activity. Here, we examined the effect of HMTM, given alone or in combination with the acetylcholinesterase inhibitor, rivastigmine, at the level of expression of selected pre-synaptic proteins (syntaxin-1; SNAP-25, VAMP-2, synaptophysin-1, synapsin-1, α-synuclein) in brain tissue harvested from tau-transgenic Line 1 (L1) and wild-type mice using immunohistochemistry. L1 mice overexpress the tau-core unit that induces tau aggregation and results in an AD-like phenotype. Synaptic proteins were lower in hippocampus and cortex but greater in basal forebrain regions in L1 compared to wild-type mice. HMTM partially normalised the expression pattern of several of these proteins in basal forebrain. This effect was diminished when HMTM was administered in combination with rivastigmine, where mean protein expression seemed supressed. This was further confirmed by group-based correlation network analyses where important levels of co-expression correlations in basal forebrain regions were lost in L1 mice and partially re-established when HMTM was given alone but not in combination with rivastigmine. These data indicate a reduction in pharmacological activity of HMTM when given as an add-on therapy, a result that is consistent with the responses observed in the clinic. Attenuation of the therapeutic effects of HMTM by cholinergic treatments may have important implications for other potential AD therapies.
Topics: Animals; Tauopathies; Mice, Transgenic; Disease Models, Animal; Cholinesterase Inhibitors; Rivastigmine; Mice; tau Proteins; Synapses; Brain; Alzheimer Disease; Male; Methylene Blue
PubMed: 38677558
DOI: 10.1016/j.brainresbull.2024.110955 -
International Journal of Molecular... Apr 2024Mild traumatic brain injury (mTBI) affects millions of people in the U.S. Approximately 20-30% of those individuals develop adverse symptoms lasting at least 3 months....
Mild traumatic brain injury (mTBI) affects millions of people in the U.S. Approximately 20-30% of those individuals develop adverse symptoms lasting at least 3 months. In a rat mTBI study, the closed-head impact model of engineered rotational acceleration (CHIMERA) produced significant axonal injury in the optic tract (OT), indicating white-matter damage. Because retinal ganglion cells project to the lateral geniculate nucleus (LGN) in the thalamus through the OT, we hypothesized that synaptic density may be reduced in the LGN of rats following CHIMERA injury. A modified SEQUIN (synaptic evaluation and quantification by imaging nanostructure) method, combined with immunofluorescent double-labeling of pre-synaptic (synapsin) and post-synaptic (PSD-95) markers, was used to quantify synaptic density in the LGN. Microglial activation at the CHIMERA injury site was determined using Iba-1 immunohistochemistry. Additionally, the effects of ketamine, a potential neuroprotective drug, were evaluated in CHIMERA-induced mTBI. A single-session repetitive (ssr-) CHIMERA (3 impacts, 1.5 joule/impact) produced mild effects on microglial activation at the injury site, which was significantly enhanced by post-injury intravenous ketamine (10 mg/kg) infusion. However, ssr-CHIMERA did not alter synaptic density in the LGN, although ketamine produced a trend of reduction in synaptic density at post-injury day 4. Further research is necessary to characterize the effects of ssr-CHIMERA and subanesthetic doses of intravenous ketamine on different brain regions and multiple time points post-injury. The current study demonstrates the utility of the ssr-CHIMERA as a rodent model of mTBI, which researchers can use to identify biological mechanisms of mTBI and to develop improved treatment strategies for individuals suffering from head trauma.
Topics: Animals; Ketamine; Microglia; Rats, Sprague-Dawley; Rats; Male; Synapses; Head Injuries, Closed; Axons; Disease Models, Animal; Geniculate Bodies; Brain Concussion; Disks Large Homolog 4 Protein; Synapsins; Neuroprotective Agents
PubMed: 38673871
DOI: 10.3390/ijms25084287 -
Frontiers in Synaptic Neuroscience 2024Rapid, synapse-specific neurotransmission requires the precise alignment of presynaptic neurotransmitter release and postsynaptic receptors. How postsynaptic glutamate...
Rapid, synapse-specific neurotransmission requires the precise alignment of presynaptic neurotransmitter release and postsynaptic receptors. How postsynaptic glutamate receptor accumulation is induced during maturation is not well understood. We find that in cultures of dissociated hippocampal neurons at 11 days (DIV) numerous synaptic contacts already exhibit pronounced accumulations of the pre- and postsynaptic markers synaptotagmin, synaptophysin, synapsin, bassoon, VGluT1, PSD-95, and Shank. The presence of an initial set of AMPARs and NMDARs is indicated by miniature excitatory postsynaptic currents (mEPSCs). However, AMPAR and NMDAR immunostainings reveal rather smooth distributions throughout dendrites and synaptic enrichment is not obvious. We found that brief periods of Ca influx through NMDARs induced a surprisingly rapid accumulation of NMDARs within 1 min, followed by accumulation of CaMKII and then AMPARs within 2-5 min. Postsynaptic clustering of NMDARs and AMPARs was paralleled by an increase in their mEPSC amplitudes. A peptide that blocked the interaction of NMDAR subunits with PSD-95 prevented the NMDAR clustering. NMDAR clustering persisted for 3 days indicating that brief periods of elevated glutamate fosters permanent accumulation of NMDARs at postsynaptic sites in maturing synapses. These data support the model that strong glutamatergic stimulation of immature glutamatergic synapses results in a fast and substantial increase in postsynaptic NMDAR content that required NMDAR binding to PSD-95 or its homologues and is followed by recruitment of CaMKII and subsequently AMPARs.
PubMed: 38660466
DOI: 10.3389/fnsyn.2024.1291262 -
Scientific Reports Apr 2024Ticks are obligatory voracious blood feeders infesting diverse vertebrate hosts, that have a crucial role in the transmission of diverse pathogens that threaten human...
Ticks are obligatory voracious blood feeders infesting diverse vertebrate hosts, that have a crucial role in the transmission of diverse pathogens that threaten human and animal health. The continuous emergence of tick-borne diseases due to combined worldwide climatic changes, human activities, and acaricide-resistant tick strains, necessitates the development of novel ameliorative tick control strategies such as vaccines. The synchrotron-based Fourier transform infrared micro-spectroscopy (SR-FTIR) is a bioanalytical microprobe capable of exploring the molecular chemistry within microstructures at a cellular or subcellular level and is considered as a nondestructive analytical approach for biological specimens. In this study, SR-FTIR analysis was able to explore a qualitative and semi-quantitative biochemical composition of gut and salivary glands of Hyalomma dromedarii (H. dromedarii) tick detecting differences in the biochemical composition of both tissues. A notable observation regarding Amide I secondary structure protein profile was the higher ratio of aggregated strands in salivary gland and beta turns in gut tissues. Regarding the lipid profile, there was a higher intensity of lipid regions in gut tissue when compared to salivary glands. This detailed information on the biochemical compositions of tick tissues could assist in selecting vaccine and/or control candidates. Altogether, these findings confirmed SR-FTIR spectroscopy as a tool for detecting differences in the biochemical composition of H. dromedarii salivary glands and gut tissues. This approach could potentially be extended to the analysis of other ticks that are vectors of important diseases such as babesiosis and theileriosis.
Topics: Animals; Humans; Spectroscopy, Fourier Transform Infrared; Ixodidae; Acaricides; Salivary Glands; Synapsins; Lipids
PubMed: 38609442
DOI: 10.1038/s41598-024-59165-6