7 replies to this topic

[APBT]

  

 

Abstract

Physical exercise has emerged as an alternative treatment for patients with depressive disorder. Recent animal studies show that exercise protects from depression by increased skeletal muscle kynurenine aminotransferase (KAT) expression which shifts the kynurenine metabolism away from the neurotoxic kynurenine (KYN) to the production of kynurenic acid (KYNA). In the present study, we investigated the effect of exercise on kynurenine metabolism in humans. KAT gene and protein expression was increased in the muscles of endurance-trained subjects compared with untrained subjects. Endurance exercise caused an increase in plasma KYNA within the first hour after exercise. In contrast, a bout of high-intensity eccentric exercise did not lead to increased plasma KYNA concentration. Our results show that regular endurance exercise causes adaptations in kynurenine metabolism which can have implications for exercise recommendations for patients with depressive disorder.

Copyright © 2016 the American Physiological Society.

https://www.ncbi.nlm...pubmed/27030575

 

 

FULL TEXT:

Attached Files

•  Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans.pdf   237KB   1 downloads

[gamesguru]

brb.  hitting the gym and misc bodybuilding forum.  back.  they said exercise is also good for a buttload of other things, and everyone should be doing it.

 

(S)-4-(Ethylsulfonyl)benzoylalanine is a potent and selective inhibitor of kynurenine aminotransferase

 

it's not clear which agent is harmful, if either.

Br J Pharmacol. 1998 May;124(2):391-9.

Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid.

Harris CA¹, Miranda AF, Tanguay JJ, Boegman RJ, Beninger RJ, Jhamandas K.

Abstract

1. Nicotinylalanine, an inhibitor of kynurenine metabolism, has been shown to elevate brain levels of endogenous kynurenic acid, an excitatory amino acid receptor antagonist. This study examined the potential of nicotinylalanine to influence excitotoxic damage to striatal NADPH diaphorase (NADPH-d) and gamma-aminobutyric acid (GABA)ergic neurones that are selectively lost in Huntington's disease. 2. A unilateral injection of the N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid, into the rat striatum produced an 88% depletion of NADPH-d neurones. Intrastriatal infusion of quinolinic acid also produced a dose-dependent reduction in striatal GABA content. 3. Nicotinylalanine (2.3, 3.2, 4.6, 6.4 nmol 5 microl(-1), i.c.v.) administered with L-kynurenine (450 mg kg(-1)), a precursor of kynurenic acid, and probenecid (200 mg kg(-1)), an inhibitor of organic acid transport, 3 h before the injection of quinolinic acid (15 nmol) produced a dose-related attenuation of the quinolinic acid-induced loss of NADPH-d neurones. Nicotinylalanine (5.6 nmol 5 microl(-1)) in combination with L-kynurenine and probenecid also attenuated quinolinic acid-induced reductions in striatal GABA content. 4. Nicotinylalanine (4.6 nmol, i.c.v.), L-kynurenine alone or L-kynurenine administered with probenecid did not attenuate quinolinic acid-induced depletion of striatal NADPH-d neurones. However, combined administration of kynurenine and probenecid did prevent quinolinic acid-induced reductions in ipsilateral striatal GABA content. 5. Injection of nicotinylalanine, at doses (4.6 nmol and 5.6 nmol i.c.v.) which attenuated quinolinic acid-induced striatal neurotoxicity, when combined with L-kynurenine and probenecid produced increases in both whole brain and striatal kynurenic acid levels. Administration of L-kynurenine and probenecid without nicotinylalanine also elevated kynurenic acid, but to a lesser extent. 6. The results of this study demonstrate that nicotinylalanine has the potential to attenuate quinolinic acid-induced striatal neurotoxicity. It is suggested that nicotinylalanine exerts its effect by increasing levels of endogenous kynurenic acid in the brain. The results of this study suggest that agents which influence levels of endogenous excitatory amino acid antagonists such as kynurenic acid may be useful in preventing excitotoxic damage to neurones in the CNS.

 

 

black tea.  not so hot.

BBA Clin. 2015 Jun; 3: 31–35.

Regular consumption of black tea increases circulating kynurenine concentrations: A randomized controlled trial^☆

J.M. Gostner,^aK. Becker,^bK.D. Croft,^c  et al.

Abstract Background

Circulating neopterin and the ratio of kynurenine to tryptophan (KYN/TRP) concentrations are biomarkers of immune activation that have been linked to cardiovascular and total mortality. Several in vitro studies indicated that tea flavonoids and other antioxidants can modulate tryptophan breakdown rates and neopterin production in immune cells. We aimed to assess the effects of regular black tea consumption on tryptophan and neopterin metabolisms in vivo.

Methods

Participants were healthy individuals, with no major illnesses and having normal to mildly elevated systolic blood pressure. They were randomly assigned to consume 3 cups/day of either powdered black tea solids (tea; n = 45) or a flavonoid-free caffeine-matched beverage (control; n = 49). Serum concentrations of tryptophan, kynurenine and neopterin were assessed at baseline and again at 3 and 6 months after daily ingestion of the respective beverage.

Results

Regular consumption of tea over 6 months, compared to control, did not significantly alter neopterin (p = 0.13) or tryptophan (p = 0.85) concentrations, but did result in significantly higher kynurenine (p = 0.016) and KYN/TRP (p = 0.012). Relative to the control group, in the tea group kynurenine and KYN/TRP increased during the treatment period by 0.28 μmol/L (95% CI: − 0.04, 0.60) and 3.2 μmol/mmol (95% CI: − 1.6, 8.0), respectively at 3 months, and by 0.48 μmol/L (95% CI: 0.16, 0.80) and 7.5 μmol/mmol (95% CI: 2.5, 12.5), respectively at 6 months.

Conclusions

Increased circulation of kynurenine and KYN/TRP following regular black tea consumption may indicate enhanced tryptophan breakdown, possibly due to immune activation-induced tryptophan degrading enzyme indoleamine 2,3-dioxygenase.

General significance

The influence of black tea consumption on biomarkers of immune system activation could relate to its general health benefits. Data suggests that the net effect strongly depends on the individual immune state, being stimulatory in healthy individuals, while acting more immune dampening in situations with an inflammatory background.

 

 

galantamine.

Neuroscience. 2013 May 15;238:19-28. doi: 10.1016/j.neuroscience.2013.01.063. Epub 2013 Feb 6.

Early developmental elevations of brain kynurenic acid impair cognitive flexibility in adults: reversal with galantamine.

Alexander KS1, Pocivavsek A, Wu HQ, Pershing ML, Schwarcz R, Bruno JP.

Author information

Abstract

Levels of kynurenic acid (KYNA), an endogenous α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, are elevated in the brain of patients with schizophrenia (SZ) and might contribute to the pathophysiology and cognitive deficits seen in the disorder. As developmental vulnerabilities contribute to the etiology of SZ, we determined, in rats, the effects of perinatal increases in KYNA on brain chemistry and cognitive flexibility. KYNA's bioprecursor l-kynurenine (100mg/day) was fed to dams from gestational day 15 to postnatal day 21 (PD21). Offspring were then given regular chow until adulthood. Control rats received unadulterated mash. Brain tissue levels of KYNA were measured at PD2 and PD21, and extracellular levels of KYNA and glutamate were determined by microdialysis in the prefrontal cortex in adulthood (PD56-80). In other adult rats, the effects of perinatal l-kynurenine administration on cognitive flexibility were assessed using an attentional set-shifting task. l-Kynurenine treatment raised forebrain KYNA levels ∼3-fold at PD2 and ∼2.5-fold at PD21. At PD56-80, extracellular prefrontal KYNA levels were moderately but significantly elevated (+12%), whereas extracellular glutamate levels were not different from controls. Set-shifting was selectively impaired by perinatal exposure to l-kynurenine, as treated rats acquired the discrimination and intra-dimensional shift at the same rate as controls, yet exhibited marked deficits in the initial reversal and extra-dimensional shift. Acute administration of the α7nAChR-positive modulator galantamine (3.0mg/kg, i.p.) restored performance to control levels. These results validate early developmental exposure to l-kynurenine as a novel, naturalistic animal model for studying cognitive deficits in SZ.

 

http://www.ncbi.nlm....les/PMC3666324/

Psychopharmacology (Berl). 2012 Apr;220(3):627-37. doi: 10.1007/s00213-011-2539-2. Epub 2011 Oct 26.

Acute elevations of brain kynurenic acid impair cognitive flexibility: normalization by the alpha7 positive modulator galantamine.

Alexander KS1, Wu HQ, Schwarcz R, Bruno JP.

Author information

Abstract

RATIONALE: 

Cognitive deficits represent a core symptom cluster in schizophrenia (SZ) that is predictive of outcome but not effectively treated by current antipsychotics. Thus, there is a need for validated animal models for testing potential pro-cognitive drugs.

OBJECTIVE: 

As kynurenic acid levels are increased in prefrontal cortex (PFC) of individuals with SZ, we acutely increased brain levels of this astrocyte-derived, negative modulator of alpha7 nicotinic acetylcholine receptors (α7nAChRs) by administration of its bioprecursor kynurenine and measured the effects on extracellular kynurenic acid and glutamate levels in PFC and also performance in a set-shifting task.

RESULTS: 

Injections of kynurenine (100 mg/kg, i.p.) increased extracellular kynurenic acid (1,500%) and decreased glutamate levels (30%) in PFC. Kynurenine also produced selective deficits in set-shifting. Saline- and kynurenine-treated rats similarly acquired the compound discrimination and intra-dimensional shift (saline, 7.0 and 6.3 trials, respectively; kynurenine, 8.0 and 6.7). Both groups required more trials to acquire the initial reversal (saline, 15.3; kynurenine, 22.2). Only kynurenine-treated rats were impaired in acquiring the extra-dimensional shift (saline, 8.2; kynurenine, 21.3). These deficits were normalized by administering the α7nAChR positive allosteric modulator galantamine (3.0 mg/kg, i.p) prior to kynurenine, as trials were comparable between galantamine + kynurenine (7.8) and controls (8.2). Bilateral local perfusion of the PFC with galantamine (5.0 μM) also attenuated kynurenine-induced deficits.

CONCLUSIONS: 

These results validate the use of animals with elevated brain kynurenic acid levels in SZ research and support studies of drugs that normalize brain kynurenic acid levels and/or positively modulate α7nAChRs as pro-cognitive treatments for SZ.

 

 

ginkgo.

J Neurochem. 2001 May;77(4):1108-15.

6-Hydroxykynurenic acid and kynurenic acid differently antagonise AMPA and NMDA receptors in hippocampal neurones.

Weber M¹, Dietrich D, Gräsel I, Reuter G, Seifert G, Steinhäuser C.

Abstract

6-Hydroxykynurenic acid (6-HKA), a derivative of kynurenic acid (KYNA) extracted from Ginkgo biloba leaves, was tested for its putative glutamate receptor (GluR) antagonism in comparison to the scaffold substance. The patch-clamp method together with fast-application techniques were used to estimate inhibition by 6-HKA and KYNA of agonist binding at NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (NMDARs and AMPARs) of CA1 pyramidal neurones. 6-Hydroxykynurenic acid proved to be a low-affinity antagonist. When comparing with KYNA, 6-HKA was less potent at NMDARs (IC(50) = 136 versus 59 microM), but showed a higher affinity to AMPARs (K(B) = 22 versus 172 microM). The replacement of 6-HKA and KYNA by glutamate was investigated on outside-out patches. Both antagonists competitively inhibited AMPAR responses and displayed fast unbinding kinetics, but the derivative was significantly slower displaced than KYNA (tau = 1.63 versus 1.22 ms). Our findings demonstrate that 6-hydroxylation considerably changes the pharmacological profile of KYNA. Among the 6-derivatives of KYNA, 6-HKA shows the highest affinity to AMPARS: Despite its relatively low lipophily, these properties might be of clinical relevance under conditions that compromise the integrity of the blood-brain barrier. Furthermore, 6-HKA should be a useful tool to analyse glutamate-mediated synaptic responses.

 

Arch Pharm Res. 2006 Dec;29(12):1074-9.

In vitro peroxynitrite scavenging activity of 6-hydroxykynurenic acid and other flavonoids from Gingko biloba yellow leaves.

Hyun SK¹, Jung HA, Chung HY, Choi JS.

Abstract

As part of our research on phytochemicals that exert protective effects against diseases related to reactive nitrogen species, we have evaluated the scavenging activity of the yellow leaves of Ginkgo biloba on ONOO-. The methanol extract and ethyl acetate fraction obtained from yellow leaves of G. biloba evidenced a marked scavenging activity on authentic ONOO-. Repeated column chromatography of the active ethyl acetate soluble fraction on silica gel, Sephadex LH-20, and RP-18, resulted in the purification of 15 known compounds, including sciadopitysin (1), ginkgolide B (2), bilobalide (3), isoginkgetin (4), kaempferol (5), luteolin (6), protocatechuic acid (7), bilobetin (8), amentoflavone (9), beta-sitosterol glucopyranoside (10), kaempferol 3-O-rhamnopyranoside (11), kaempferol 3-O-glucopyranoside (12), kaempferol 3-O-[6"'-O-p-coumaroyl-beta-D-glucopyranosyl(1 --> 2)-alpha-L-rhamnopyranoside] (13), kaempferol 3-O-rutinoside (14), and 6-hydroxykynurenic acid (15). Among the compounds isolated, flavonoids (5, 6 and 11-14), protocatechuic acid (7), and 6-hydroxykynurenic acid (15) all exhibited marked scavenging activities on authentic ONOO-. The IC50 values of 5-7, 11-14 and 15 were as follows: 2.86 +/- 0.70, 2.30 +/- 0.04, 2.85 +/- 0.10, 5.60 +/- 0.47, 4.16 +/- 1.65, 2.47 +/- 0.15, 3.02 +/- 0.48, and 6.24 +/- 0.27 microM, respectively. DL-Penicillamine (IC50 = 4.98 +/- 0.27 microM) was utilized as a positive control. However, the other compounds (1-4, 8-10) exerted no effects against ONOO-.

 

 

ginger (a COX-2 inhibitor) may also be helpful in this context.  it also is great for heart health and boosts test by 17.7%.

 

“... the effects of COX-2 inhibition in the CNS, as well as toward different components of the inflammatory system, kynurenine metabolism and glutamatergic neurotransmission, require further evaluation, which should include clinical trials with larger numbers of patients”

 

 

lastly we have an article explaining the pathways and many RCs, as well as a one-move debate between lostfalco and I as to whether kynurenic acid is bad at all. www.longecity.org/forum/topic/80353-getting-back-on-track/

Attached Files

•  Kynurenic acid antagonists and kynurenine pathway inhibitors.pdf   176.21KB   2 downloads

[Junk Master]

Great stuff!

 

As far as endurance exercise ameliorating depression v. weights I can personally testify that NOTHING, including 5 SSRi'S, 2 SNRi's, plus 20 years of weight lifting helped lift my depression more than endurance exercise.  The key here is in my case, the sessions had to be at least 35 minutes and I didn't begin to experience "full effects" until 45 minutes and beyond.

 

Now the caveat is the exercise CAN'T be so difficult I would lose my ability to talk normally, or would feel any build up of lactic acid.  That means the vast majority of those experiencing depression aren't going to get there, again IMO-- and even those who do, will have difficulty sustaining those levels for long periods of time without injury, or as they age.

 

It's hard to describe to your "average Walmart American" it's quite possible for even a relatively large individual (190 pounds) to reach the point where running an hour to an hour and a half without ever breathing is possible.  In fact, it's not difficult to achieve a level of aerobic fitness where it's hard to lose your breath without hills if your level of exertion is kept below your lactic acid threshold.

 

Man, I miss those days!  Lol...trying to get back there at 50 is truly a worthy mental, and physical challenge.   Off to drink my hydrogen water

[jack black]

Well, for me, exercise never made me feel better, the opposite, made me more depressed. I'm not alone. If you search Google, it's fairly common.

Now, it's possible I'm doing it wrong. What would be the typical endurance training?

[Oakman]

I can't speak for anyone but myself, but absolutely exercise gives me a 'lift', or 'pump' that literally makes me feel good enough that I can't feel bad. Admittedly, I've been good weather walking @5-10 miles/week since 1995, but it wasn't until retirement in Spring 2014 @65 yr old I began what might be called 'endurance training'. Little bike rides followed by longer and longer rides took time, perseverance, and getting over a lot of beginners aches and pains, but by fall 2015 I reached cycling 400-600 mi/mo, or average ~min 130 miles/wk. This year I started strength training (weights/machines), while reducing cycling to 150-200 mi/mo. 

 

Both I consider endurance training of a sort, with cycling 20-30 miles taking 1.5-2.5 hrs and a good gym workout 1-2 hrs. Both are equally good at putting me on top of the world, mentally and physically. People who do this type of thing, know the feeling. When you stop for a few days, you really feel the dark clouds coming and just have to get back at it. It almost always feels so much better afterwards.

 

To your question, the hardest part was building up the physical endurance slowly and managing aches & pains while maintaining a nearly daily routine. Now, I look forward to the exercise, and it's become a normal part of my healthy lifestyle. I'd recommend endurance and strength training to everyone, as it some of the best longevity medicine available to all.

 

Beyond that, my feeling is that all these supplements people take need something to work at in our bodies. Exercise provides for processes of biogenesis and rejuvenation of the body, and so the need for nutrients and supplement to support them. Anything (one) sitting still, doing little physical work simply degenerates as biogenesis nearly ceases. Or at least that's a big part of my plan for healthy longevity

[jack black]

maybe this is why I feel worse after exercise:

 

 

Endurance Exercise can also reduce Testosterone levels^[7][8]

 

https://en.wikipedia...urance_training

[gamesguru]

it's not a huge reduction.  strength training increases test, but that doesn't mean it's better than cardio.  with all due respect it helps to look at things from other perspectives, other biomarkers, besides test.  maybe exercise makes you feel worse because you don't do it often, aren't properly conditioned, and become easily exhausted?

[jack black]

Now since I learned what endurance training is, I actually did that in high school as I represented the school in long distance running (I wasn't even good at it, long story). This was when I discovered bad influence of running on my mood and lost interest in physical activity. I do regular exercise everyday, mostly walking 2 miles and more on weekends, but I don't enjoy it. And yes I'm being treated for low T.