Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid

Tóth, Ferenc; Cseh, Edina Katalin; Vécsei, László

doi:10.3390/ijms22010403

Cited by 41 publications

(16 citation statements)

References 201 publications

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“…Excitotoxicity produces an initial phase of cell swelling of neurons that precedes cell death (Choi, 1985 ; Choi et al, 1987 ; Ramnath et al, 1992 ; Churchwell et al, 1996 ). Kynurenic acid is an antagonist of all ionotropic glutamate receptors and is known to prevent excitotoxicity (Ganong et al, 1983 ; Foster et al, 1984 ; Espanol et al, 1994 ; Pozzo Miller et al, 1994 ; Urenjak and Obrenovitch, 2000 ; Feher et al, 2019 ; Toth et al, 2021 ). We added kynurenic acid (3 mM) to the recovery ACSF after slicing to attempt to prevent possible excitotoxicity in the synGLT-1 KO acute hippocampal slices.…”

Section: Resultsmentioning

confidence: 99%

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

Rimmele

Andersen

et al. 2021

Front. Cell. Neurosci.

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GLT-1, the major glutamate transporter in the mammalian central nervous system, is expressed in presynaptic terminals that use glutamate as a neurotransmitter, in addition to astrocytes. It is widely assumed that glutamate homeostasis is regulated primarily by glutamate transporters expressed in astrocytes, leaving the function of GLT-1 in neurons relatively unexplored. We generated conditional GLT-1 knockout (KO) mouse lines to understand the cell-specific functions of GLT-1. We found that stimulus-evoked field extracellular postsynaptic potentials (fEPSPs) recorded in the CA1 region of the hippocampus were normal in the astrocytic GLT-1 KO but were reduced and often absent in the neuronal GLT-1 KO at 40 weeks. The failure of fEPSP generation in the neuronal GLT-1 KO was also observed in slices from 20 weeks old mice but not consistently from 10 weeks old mice. Using an extracellular FRET-based glutamate sensor, we found no difference in stimulus-evoked glutamate accumulation in the neuronal GLT-1 KO, suggesting a postsynaptic cause of the transmission failure. We hypothesized that excitotoxicity underlies the failure of functional recovery of slices from the neuronal GLT-1 KO. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist MK801, when present in the ACSF during the recovery period following cutting of slices, promoted full restoration of fEPSP generation. The inclusion of an enzymatic glutamate scavenging system in the ACSF conferred partial protection. Excitotoxicity might be due to excess release or accumulation of excitatory amino acids, or to metabolic perturbation resulting in increased vulnerability to NMDA receptor activation. Previous studies have demonstrated a defect in the utilization of glutamate by synaptic mitochondria and aspartate production in the synGLT-1 KO in vivo, and we found evidence for similar metabolic perturbations in the slice preparation. In addition, mitochondrial cristae density was higher in synaptic mitochondria in the CA1 region in 20–25 weeks old synGLT-1 KO mice in the CA1 region, suggesting compensation for loss of axon terminal GLT-1 by increased mitochondrial efficiency. These data suggest that GLT-1 expressed in presynaptic terminals serves an important role in the regulation of vulnerability to excitotoxicity, and this regulation may be related to the metabolic role of GLT-1 expressed in glutamatergic axon terminals.

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Section: Resultsmentioning

confidence: 99%

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

Rimmele

Andersen

et al. 2021

Front. Cell. Neurosci.

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“…Several clinical studies on peripheral neuropathies confirmed positive results in terms of symptom relief (pain, allodynia, dysesthesia, paresthesia) and patient safety. 8,14 L-acetylcarnitine is the acetyl ester of L-carnitine, which plays an essential role in the metabolism of fatty acids in mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Integration with Spilanthes Achmella in fibromyalgia syndrome: open-label study six months after the treatment

et al. 2021

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Fibromyalgia, also known as fibromyalgia syndrome (FM), is a rheumatic syndrome which is currently considered idiopathic and multifactorial. It causes an increase in muscle tension associated with stiffness, asthenia (loss of strength with fatigue), cognitive impairment, insomnia or sleep disorders and impaired sensitivity to stimuli. We performed a prospective evaluation of 149 patients suffering from fibromyalgia syndrome according to the 2010 ACR Criteria. Patients were clinically assessed at baseline and after 1-3-6 months, using the patient-reported outcomes thermometer - 5-item scale (5TPROs). In addition to their therapy, all patients received a supplementation with Spilanthes Achmella. This food supplement is characterized by synergy of bioactive compounds, such as Acmella oleracea extract, and has neurotrophic, anti-inflammatory and pain-relieving effects. All patients were randomized at baseline to receive Spilanthes Achmella, 2 tablets per day for one month and subsequent tapering to 1 tablet per day for 5 months. At six months, a statistically significant difference in the following parameters was shown: pain P<0.001, fatigue P<0.001, physical function P<0.001, depression: P<0.001, general health P<0.001. Conversely, the post-hoc analysis data did not report any significant difference for the parameters between the third and sixth month. A drug-sparing effect was observed (P<0.001). The posthoc analysis revealed a significant difference between T0 and T3 P=0.00066 and between T0 and T6 P=0.00008. Our data indicate that supplementation with Spilanthes Achmella may lead to a significant improvement in pain, fatigue, physical function, depression and general health in fibromyalgia syndrome.

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“…Second, another approach would be to increase KA activity by administration of specific diets [47], KA supplements and a ketogenic diet, which may increase KA levels [48], or KA analogs [49]. However, KA itself has limited ability to cross the BBB [42] and treatment with KA enhancing strategies is also not evident because KA may interact with several receptors in the CNS, and influence various neurotransmitter systems [50]. Hopefully, the new precision psychiatry approach will eventually reveal the best drug targets in the TRYCAT pathway to treat specific endophenotypes of depression.…”

Section: Future Treatmentsmentioning

confidence: 99%

The Tryptophan Catabolite or Kynurenine Pathway’s Role in Major Depression

Almulla¹,

Maes²

2022

Preprint

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Kynurenine or tryptophan catabolite (TRYCAT) pathway contributes to the pathophysiology of major depression disorder (MDD) and major depressive episodes (MDE) in bipolar disorder and suicidal behaviors. The consequences of the overactivation of this pathway large reduced tryptophan (TRP) levels in peripheral blood and the CNS and increased levels of neurotoxic TRYCATs including kynurenine (KYN), 3-hydroxy kynurenine (3HK), quinolinic acid (QA), xanthurenic acid (XA), and picolinic acid (PA). However, other TRYCATs are protective, such as kynurenic acid (KA) and anthranilic acid (AA). Inflammation and cell-mediated immune activation along with oxidative and nitrosative stress (O&NS) may stimulate the first and rate-limiting enzyme of this pathway, namely indoleamine-2,3-dioxygenase (IDO). Therefore, during depression, balancing neuroprotective versus neurotoxic TRYCATs and balancing activation of the immune response system (IRS) versus the compensatory immune response system is crucial for achieving better treatment outcomes. Furthermore, targeting the causes of TRYCAT pathway activation (immune activation and O&NS) is probably the most effective strategy to treat depression. In the present review, we aim to provide a comprehensive explanation of the impact of TRYCATs in terms of pathophysiology and treatment of MDD and MDE.

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Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid

Cited by 41 publications

References 201 publications

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

Integration with Spilanthes Achmella in fibromyalgia syndrome: open-label study six months after the treatment

The Tryptophan Catabolite or Kynurenine Pathway’s Role in Major Depression

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