Neurodegenerative disorders, e.g. Parkinson's, Huntington's and Alzheimer's diseases are distinct clinical and pathological entities sharing a number of leading features in their underlying ...processes. These common features involve the disturbances in the normal functioning of the mitochondria and the alterations in the delicate balance of tryptophan metabolism. The development of agents capable of halting the progression of these diseases is in the limelight of neuroscience research. This review highlights the role of mitochondria in the development of neurodegenerative processes with special focus on the involvement of neuroactive kynurenines both as pathological agents and potential targets and tools for future therapeutic approaches by providing a comprehensive summary of the main streams of rational drug design and giving an insight into present clinical achievements.
Core-shell nanoparticles (CSNPs) were developed to get over therapeutic amount of kynurenic acid (KYNA) across the blood–brain barrier (BBB). Bovine serum albumin (BSA) was used as core for ...encapsulation of KYNA and the BSA/KYNA composite was finally encapsulated by poly(allylamine) hydrochloride (PAH) polymer as shell. In the interest of the optimization of the synthesis the BSA and KYNA interaction was studied by two-dimensional surface plasmon resonance (SPR) technique as well. The average size of d~100nm was proven by dynamic light scattering (DLS) and transmission electron microscopy (TEM), while the structure of the composites was characterized by fluorescence (FL) and circular dichroism (CD) spectroscopy. The in vitro release properties of KYNA were investigated by a vertical diffusion cell at 25.0°C and 37.5°C and the kinetic of the release were discussed. The penetration capacity of the NPs into the central nervous system (CNS) was tested by an in vitro BBB model. The results demonstrated that the encapsulated KYNA had significantly higher permeability compared to free KYNA molecules. In the neurobiological serial of in vivo experiments the effects of peripherally administered KYNA with CSNPs were studied in comparison with untreated KYNA. These results clearly proved that KYNA in the CSNPs, administrated peripherally is suitable to cross the BBB and to induce electrophysiological effects within the CNS. As the neuroprotective properties of KYNA nowadays are proven, the importance of the results is obvious.
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Background
Migraine is a debilitating neurological disorder where trigeminovascular activation plays a key role. We have previously reported that local application of Complete Freund’s Adjuvant (CFA) ...onto the dura mater caused activation in rat trigeminal ganglion (TG) which was abolished by a systemic administration of kynurenic acid (KYNA) derivate (SZR72). Here, we hypothesize that this activation may extend to the trigeminal complex in the brainstem and is attenuated by treatment with SZR72.
Methods
Activation in the trigeminal nucleus caudalis (TNC) and the trigeminal tract (Sp5) was achieved by application of CFA onto the dural parietal surface. SZR72 was given intraperitoneally (i.p.), one dose prior CFA deposition and repeatedly daily for 7 days. Immunohistochemical studies were performed for mapping glutamate, c-fos, PACAP, substance P, IL-6, IL-1β and TNFα in the TNC/Sp5 and other regions of the brainstem and at the C
1
-C
2
regions of the spinal cord.
Results
We found that CFA increased c-fos and glutamate immunoreactivity in TNC and C
1
-C
2
neurons. This effect was mitigated by SZR72. PACAP positive fibers were detected in the fasciculus cuneatus and gracilis. Substance P, TNFα, IL-6 and IL-1β immunopositivity were detected in fibers of Sp5 and neither of these molecules showed any change in immunoreactivity following CFA administration.
Conclusion
This is the first study demonstrating that dural application of CFA increases the expression of c-fos and glutamate in TNC neurons. Treatment with the KYNA analogue prevented this expression.
The syntheses and transformations of 4-hydroxyquinoline-2-carboxylic acid, kynurenic acid, are reviewed, and special attention is paid to the pharmacological activities and pharmaceutical ...applications of its derivatives.
Highlights • ALC restores impaired LTP to the control level in the ischemic hippocampus. • As a result, the spine density of CA1 pyramidal cells normalizes. • This is the first demonstration that ALC ...can induce spine genesis in the CA1 region. • ALC can be administered safely, even at high doses. • ALC does not influence normal LTP in healthy rats.
Background
The trigeminal ganglion (TG) plays a central role in cranial pain. Administration of complete Freund’s adjuvant (CFA) into the temporomandibular joint (TMJ) elicits activation of TG. ...Kynurenic acid (KYNA) is an endogenous excitatory amino acid receptor blocker, which may have an anti-inflammatory effect. We hypothesize that KYNA may reduce CFA-induced activation within the TG.
Methods
A local inflammation was induced by administration of CFA into the TMJ in rats. KYNA and kynurenic acid amide 2 (KYNAA2) were intraperitoneally administered. We investigated changes of mitogen-activated protein kinases (MAPKs as ERK1/2, p38 and SAPK/JNK), NF-κB, CaMKII and DREAM, in addition to calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in the TG, with immunohistochemistry and Western blot at 2 and 10 days post-CFA injection.
Results
We showed CFA-induces increases in pERK1/2, pp38, CaMKII, NF-κB and DREAM immunohistochemistry after 2 and 10 days. KYNAA2 displayed stronger effects on MAPKs than KYNA. Increased expression of CaMKII, NF-κB and DREAM were found in the neurons. Western blot showed significantly increase in pERK expression at 10 days post-CFA, which decreased after 10 days of KYNA treatment. Two days post-CFA, a significantly increase in pp38 expression was found, which decreased after 2 days of KYNA and KYNAA2 treatment.
Conclusions
The CFA-induced inflammatory model for the TG activation provided a time-related expression of MAPK (pERK1/2, pp38) and NF-κB. It involves both the neuronal and glial activation, which points to possible neuron-glia interactions during this process. The administration of the endogenous NMDA-receptor antagonists, KYNA and its derivative KYNAA2, resulted in the inhibition of the induced signaling system of the TG, which further points the importance of the glutamate receptors in this mechanism.
Background
Neurogenic inflammation has for decades been considered an important part of migraine pathophysiology. In the present study, we asked the question if administration of a novel kynurenic ...acid analogue (SZR72), precursor of an excitotoxin antagonist and anti-inflammatory substance, can modify the neurogenic inflammatory response in the trigeminal ganglion.
Methods
Inflammation in the trigeminal ganglion was induced by local dural application of Complete Freunds Adjuvant (CFA). Levels of phosphorylated MAP kinase pERK1/2 and IL-1β expression in V1 region of the trigeminal ganglion were investigated using immunohistochemistry and Western blot.
Findings
Pretreatment with one dose of SZR72 abolished the CFA-induced pERK1/2 and IL-1β activation in the trigeminal ganglion. No significant change was noted in case of repeated treatment with SZR72 as compared to a single dose.
Conclusions
This is the first study that demonstrates that one dose of KYNA analog before application of CFA can give anti-inflammatory response in a model of trigeminal activation, opening a new line for further investigations regarding possible effects of KYNA derivates.
Administration of nitroglycerol in a migraine model results in an increased number of
c-fos-expressing secondary sensory neurons in the caudal trigeminal nucleus. Since synapses between first- and ...second-order trigeminal neurons are mediated by excitatory amino acids, NMDA receptors are inhibited by kynurenic acid, though this crosses the blood–brain barrier only poorly. Systemic treatment of rats with SZR-72, a newly synthetized kynurenic acid analog, diminished the nitroglycerol-induced increase of
c-fos immunoreactivity in the brain stem highly significantly, while treatment with kynurenic acid resulted in a significantly smaller decrease, proving that SZR-72 is much more effective than kynurenic acid.
During an ischemic event, the well-regulated glutamate (Glu) homeostasis is disturbed, which gives rise to extremely high levels of this excitatory neurotransmitter in the brain tissues. It was ...earlier reported that the administration of oxaloacetate (OxAc) as a Glu scavenger reduces the Glu level in the brain by enhancing the brain-to-blood Glu efflux. Here, we studied the neuroprotective effect of OxAc administration in a new focal ischemic model in rats. Occlusion of the middle cerebral artery resulted in immediate reduction of the somatosensory-evoked responses (SERs), and the amplitudes remained at the reduced level throughout the whole ischemic period. On reperfusion, the SERs started to increase, but never reached the control level. OxAc proved to be protective, since the amplitudes started to recover even during the ischemia, and finally fully regained the control level. The findings of the histological measurements were in accordance with the electrophysiological data. After Fluoro Jade C staining, significantly fewer labeled cells were detected in the OxAc-treated group relative to the control. These results provide new evidence of the neuroprotective effect of OxAc against ischemic injury, which strengthens the likelihood of its future applicability as a novel neuroprotective agent for the treatment of ischemic stroke patients.
Parkinson’s, Alzheimer’s and Huntington’s diseases are chronic neurodegenerative disorders of a progressive nature which lead to a considerable deterioration of the quality of life. Their ...pathomechanisms display some common features, including an imbalance of the tryptophan metabolism. Alterations in the concentrations of neuroactive kynurenines can be accompanied by devastating excitotoxic injuries and metabolic disturbances. From therapeutic considerations, possibilities that come into account include increasing the neuroprotective effect of kynurenic acid, or decreasing the levels of neurotoxic 3-hydroxy-
l
-kynurenine and quinolinic acid. The experimental data indicate that neuroprotection can be achieved by both alternatives, suggesting opportunities for further drug development in this field.
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