![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 8 to 32 of 44. Go back in thread:
Posted by Phil on January 2, 2013, at 11:51:40
In reply to Re: More evidence of inflammation and depression. » Phil, posted by gadchik on January 2, 2013, at 10:58:24
I don't care about sex right now but I don't care about shooting guns either. Still if I needed to it would be nice to have bullets. (turns red)
I blazed a trail from 20 to around 35. Alcohol was the engine. I could walk into a club, have a few drinks, and I became animated. I was quite good looking in those days and had my choice. I had absolutely no fear.
Somewhere towards the end of that run the one night stands became very depressing. When I quit drinking I became a bit more realistic.
While it lasted it was a lot of fun. Pre-Aids. No ethics.
Posted by SLS on January 2, 2013, at 11:55:19
In reply to More evidence of inflammation and depression., posted by SLS on January 2, 2013, at 7:54:16
> "The results also support the initiation of intervention studies to examine whether adding anti-inflammatory drugs to antidepressants for treatment of depression will improve outcome," they write.
This is an ongoing study comparing the antidepressant potential of minocycline and aspirin:
Minocycline and Aspirin in the Treatment of Bipolar Depression
http://clinicaltrials.gov/show/NCT01429272
- Scott
Posted by brynb on January 2, 2013, at 11:58:26
In reply to More evidence of inflammation and depression., posted by SLS on January 2, 2013, at 7:54:16
Scott,
It makes a lot of sense. I don't know about other antibiotics, but I've been sick all month, and I've been on Keflex (cephalexin) for a week and a half and I think it's been helping this recent depressive period.
Thanks for the info.
b
Posted by Phil on January 2, 2013, at 11:58:51
In reply to Re: More evidence of inflammation and depression., posted by SLS on January 2, 2013, at 11:55:19
Should I take an aspirin a day. I guess it helps with heart attacks too?
Posted by gadchik on January 2, 2013, at 12:05:25
In reply to Re: More evidence of inflammation and depression. » gadchik, posted by Phil on January 2, 2013, at 11:51:40
Well,my run ended when I fell in love. But yeah,I remember walking into a room,after a few drinks,and feeling a rush of happiness,power,I guess just dopamine being released,or something in the alcohol...had no worries,fears. I really only wanted one person to bond with for life,and so, I did...
Posted by Phil on January 2, 2013, at 12:23:38
In reply to Re: More evidence of inflammation and depression. » Phil, posted by gadchik on January 2, 2013, at 12:05:25
I left a club one night at 2 then headed to a great, big 24 hour restaurant. I walked around and saw three pretty young girls sitting in a booth. I said hi and just sat down. We had a great time.
Sunday morning I opened the paper and on the front page was a picture of one of them, Miss San Antonio. LOL
That was my thing. I didn't ask someone to dance, I just sat down at their table. I was very much an 'Arthur' kind of character. Hey, whatever closed the deal.
God knows it wasn't just me. Everybody was on the hunt. :)
Back then I drank Crown and water doubles. Two or three of those....
Posted by gadchik on January 2, 2013, at 12:34:47
In reply to Re: More evidence of inflammation and depression. » gadchik, posted by Phil on January 2, 2013, at 12:23:38
it was magical, the things that could happen in the space of one night! I felt like a social butterfly,just flitting from one drama to the next! So,did u ever run into Miss San Antonio again? Well,I must confess that I partied with Hall & Oats one crazy night,after a concert in Roanoke Va.
Posted by Phil on January 2, 2013, at 13:11:36
In reply to Re: More evidence of inflammation and depression. » Phil, posted by gadchik on January 2, 2013, at 12:34:47
You go girl!! I called her after reading the story. Stalker? I said you didn't tell me you were Miss SA. I don't remember what she said but she laughed. She was a sweetheart. If I was Mr anything I would have been slipping it into every conversation I had.
I sat down next to two ladies at an IHOP one time. They said you might want to move, our husbands are in the bathroom. I think that cured me.
I won't go into sitting with two ladies, a doctor and an RN. I talked them into going to the coast two and a half hours away. But I tell you what, it was a long night. I was absolutely sh*tfaced that night.
Posted by Phil on January 2, 2013, at 13:13:47
In reply to Re: More evidence of inflammation and depression. » Phil, posted by gadchik on January 2, 2013, at 12:34:47
Daryl Hall is a great singer and turns out a really cool musician. I never was quite sure what Oates was.
Posted by gadchik on January 2, 2013, at 13:17:22
In reply to Re: More evidence of inflammation and depression. » gadchik, posted by Phil on January 2, 2013, at 13:13:47
Posted by Emme_V2 on January 2, 2013, at 16:59:00
In reply to More evidence of inflammation and depression., posted by SLS on January 2, 2013, at 7:54:16
> I don't subscribe to the inflammation causes depression school of thought. In my mind, stress comes first, depression comes second, and inflammation comes third. Of course this is only a guess. At most, there might be a convergence. However, there are too many different non-inflammatory biomarkers associated with depression to ignore, including genetic.
Below are a couple of articles that can support the "inflammation leading to depression" directionality. (I've skimmed them quickly, but I haven't read them in detail.)
I'm sure researchers will gather more information before things are sorted out one way or the other. And of course, there are probably a number of etiologies for depression, including genetic contributions. Who knows, perhaps stress leads to inflammatory response, which helps trigger depression for Person A, while a different pathway produces depression for Person B.
http://www.ncbi.nlm.nih.gov/pubmed/22197082
http://stevebmd.files.wordpress.com/2011/04/cytokines-sing-the-blues2006.pdf
Posted by SLS on January 2, 2013, at 17:46:40
In reply to Re: More evidence of inflammation and depression. » SLS, posted by Emme_V2 on January 2, 2013, at 16:59:00
Hi Emme_V2
When you have a chance, can you excise and quote the passages that you believe are proof of directionality?
I still don't see it.
- Scott
Posted by SLS on January 2, 2013, at 19:06:43
In reply to Re: More evidence of inflammation and depression. » Emme_V2, posted by SLS on January 2, 2013, at 17:46:40
> Hi Emme_V2
>
> When you have a chance, can you excise and quote the passages that you believe are proof of directionality?
>
> I still don't see it.Perhaps I haven't made myself clear. I believe that, once established, major depressive disorder (MDD) can produce inflammation, which then contributes to the the worsening and persistence of the disease. It should be expected that there will be findings that describe the mechanics behind inflammation producing depression, otherwise my scenario wouldn't work. So far, everyone has been focusing on how inflammation might cause depression. I haven't seen any efforts made to evaluate how depression might cause inflammation. Depression causes cell damage and cell death through excitotoxicity, why would these events not provoke an immune response? They in fact, do. Microglial activation is the mechanism involved here, as this provokes the release of proinflammatory cytokines. What's more, intact neurons have a suppressive effect on inflammatory processes. Dead neurons provoke them.
I think there is an interplay between depression and inflammation. Each does not exist in a vacuum, and their contributions to the evolution of MDD are not mutually exclusive. It will take elegant study designs to tease out cause and effect. Such a study might look like this:
http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1157.1998.tb01911.x/abstract
"Conclusions: In the kindling model of epilepsy, neither DNA fragmentation nor immune responses were detected. The result indicates that epileptic seizures do not depend on the immune responses. In the KA-treated model of epilepsy, immune responses were closely related to DNA fragmentation, suggesting an association of immune responses with neuronal death. We therefore suggest that immune responses play an important role in the neuronal death process induces by KA"
Robert M. Post and others have suggested that the progression of MDD and BD operate according to a kindling model. It is no mistake that I use this study to demonstrate directionality. Seizures do not depend on inflammation, but they do cause cytotoxicity and cell death. Cell death then provokes inflammatory responses. Inflammatory processes provoked by microglial release of cytokines causes even more cell death. My guess is that a resultant sclerotic scaring of tissue focally makes the epilepsy worse.
For now, I suspect that the induction of MDD does not require inflammation.
Does inflammation promote depression? Yes.
Must inflammation exist before MDD evolves? My guess is no.
- Scott
Posted by baseball55 on January 2, 2013, at 19:13:31
In reply to Re: More evidence of inflammation and depression. » SLS, posted by SLS on January 2, 2013, at 19:06:43
If inflammation directly causes depression, then why doesn't depression lift with an anti-inflammatory drug like aspirin or ibuprofin. If anyone has put their depression into remission with an NSAID, I'd love to hear about it.
Posted by Emme_V2 on January 2, 2013, at 19:22:38
In reply to Re: More evidence of inflammation and depression. » Emme_V2, posted by SLS on January 2, 2013, at 17:46:40
> Hi Emme_V2
>
> When you have a chance, can you excise and quote the passages that you believe are proof of directionality?
>
> I still don't see it.
>
>
> - Scott
>Sure. I'm afraid it might take me a week or so before I have a chance to sit down and fully digest the content, and you will probably beat me to it. :)
But it's really not my conclusions. (If only I were that smart!) Leonard and Maes state in their abstract:
"It is concluded that depression may be the consequence of a complex interplay between CMI activation and inflammation and their sequels/concomitants which all together cause neuroprogression that further shapes the depression phenotype. Future research should employ high throughput technologies to collect genetic and gene expression and protein data from patients with depression and analyze these data by means of systems biology methods to define the dynamic interactions between the different cell signaling networks and O&NS pathways that cause depression."
And they do describe a sequence of processes and what they think needs to come next. Note that they use "may." This is a different field of science than mine, so I'll probably get a bit lost in the details without logging some study time. Since the authors worked through the info and got the thing published in a peer-reviewed journal, I figure that may have a case. Of course they may be totally wrong as well, but that will hopefully get sorted out as the science progresses. And of course, the cause of depression for one person may be completely than the cause for another person, so your idea that depression can cause in inflammatory response may hold true as well.
Posted by jono_in_adelaide on January 3, 2013, at 18:42:39
In reply to More evidence of inflammation and depression., posted by SLS on January 2, 2013, at 7:54:16
Again, this suggests to me that omega 3 fatty acids would be an usefull supplement to antidepressant drugs for a lot of people.
Posted by gadchik on January 3, 2013, at 18:53:56
In reply to Re: More evidence of inflammation and depression., posted by jono_in_adelaide on January 3, 2013, at 18:42:39
I feel a boost when I take fish oil in the morning with breakfast and vit d, and I take klonopin at night. I eat wild salmon when I can too.
Posted by jono_in_adelaide on January 3, 2013, at 19:20:58
In reply to Re: More evidence of inflammation and depression. » jono_in_adelaide, posted by gadchik on January 3, 2013, at 18:53:56
I'm not a fan of fish, so I take 4 x 1000mg fish oil capsules a day with dinner, 2 x 1000mg capsules of flaxseed oil, along with a high potency multivitamin/mineral
Posted by poser938 on January 3, 2013, at 21:39:41
In reply to More evidence of inflammation and depression., posted by SLS on January 2, 2013, at 7:54:16
I like this inflamation idea. And minocycline looks like something thast my be worth trying for myself.
Posted by SLS on January 3, 2013, at 22:59:03
In reply to Re: More evidence of inflammation and depression., posted by poser938 on January 3, 2013, at 21:39:41
The major side effect to be aware of is brain swelling. This seems to be relatively rare. Watch for headaches and double-vision.
http://www.webmd.com/brain/brain-swelling-brain-edema-intracranial-pressure?page=2
Below are excerpts from an article regarding minoycline and inflammation. It is technical, but bits and pieces are decipherable. Neuroscientists are serious about this drug.
- Scott
-------------------------------------------
Does minocycline have antidepressant effect?Chi-Un Pae a,b,*,1 , David M. Marks b, Changsu Han b,c, Ashwin A. Patkar b
14 January 2008
Abstract
Only one-third of patients undergoing monotherapy with an antidepressant achieve remission of their depressive symptoms and gain func- tional recovery. Therefore, further exploration of antidepressant mechanisms of action is important in order to facilitate the development of an- tidepressants with new modes of action. Preclinical and clinical studies have demonstrated that major depression is associated with impaired inflammatory responses and deficient neuroprotection. In this regard, we propose that the second-generation tetracycline minocycline may hold a potential as a new treatment for major depression. Emerging findings in animal and human studies of minocycline reveal that it has antidepressant-like neuroprotective and anti-inflammatory actions, and minocycline has been shown to perform as an antidepressant in an accepted animal model (forced swimming test). Anecdotal evidence supports minocyclines efficacy for augmentation of antidepressants in major depres- sive disorder. The following review describes the evidence supporting the consideration of minocycline as a potential antidepressant. We suggest that minocycline may be particularly helpful in patients with depression and comorbid cognitive impairment, as well as depression associated with organic brain disease. We also describe the antinociceptive effect of minocycline and propose a role for minocycline in the treatment of patients with major depression and prominent somatic discomfort and somatoform spectrum disorders. The lack of clinical studies of minocycline for depression is noted. Further studies of the potential therapeutic mechanism of minocycline and its therapeutic implications for major depression are warranted, and may substantially contribute to the development of newer and more effective antidepressants
3. Possible antidepressant effect of minocycline through anti-inflammatory effect:
A growing body of evidence also suggests that dysregula- tion of inflammatory processes may be a major pathophysio- logical mechanism of major depression (e.g., cytokines play a major role in bridging the nervous and immune systems). Pro-inflammatory agents have been implicated in the patho- genesis of major depression, through their direct effects on neural cells or by modulating neurotransmitters and neuropep- tides [2]. A recent preclinical study showed that stress-induced depressive symptoms in mice were associated with increased hippocampal interleukin-1 (IL-1) and that mice altered by de- letion or antagonism of the IL-1 receptor were not prone to de- pressive symptoms when subjected to stress; the study authors assert that elevated brain IL-1 is linked to depression and that reduction or inhibition of brain IL-1 has potent antidepressant effects [26]. Furthermore, the pro-inflammatory cytokine levels (e.g., TNF-a and IL-1b) were found to be consistently higher in patients with major depression than in controls [3,4], and antidepressants reversed these altered levels, dem- onstrating the immunomodulatory effect of antidepressants (TNF-a and IL-1b directly cause depression in animal models) [2]. Nitric oxide (NO) is another pro-inflammatory agent that has been shown to be increased in patients with major depres- sion, a finding that is reversed by antidepressant treatment [11]. Consistent with a potential antidepressant role, minocy- cline has demonstrated a direct inhibitory effect on the pro-in- flammatory cytokines TNF-a, IL-1b, and NO in a preclinical study. More specifically, minocycline suppressed the hypoxic upregulation of these pro-inflammatory agents in cultured rat microglial and neuronal cells [10].
4. Proven antidepressant effect of minocycline in forced swimming test
A recent study in mice evaluated the potential antidepres- sant activity of minocycline alone or in combination with tra- ditional antidepressant drugs or glutamate receptor antagonists using the time sampling method in the forced swimming test (FST). Minocycline demonstrated antidepressant-like actions in that it reduced immobility by increasing climbing behavior, and a subthreshold dose of minocycline synergized the antide- pressant actions of subthreshold doses of desipramine and glu- tamate receptor antagonists [27]. The FST is one of the most commonly used animal models to evaluate antidepressant ac- tivity, and it is sensitive to all of the major classes of antidepressant drugs [27,28]. Of note, antidepressant drugs with predominantly noradrenaline or dopamine enhancing effects reduce immobility by increasing climbing behavior in the time sampling method in the FST. Conversely, antidepressant drugs with predominantly serotonin enhancing effects reduce immobility by increasing swimming [27,29]. Hence, the finding by Molina-Hernandez and colleagues [27] suggests that minocycline produces antidepressant effects through modification of the noradrenergic system in the brain. Interestingly, minocycline did not synergize the antidepressant-like actions of fluoxetine, indicating that minocycline may not directly impact the serotonergic system [27]. Accordingly, as the authors propose, minocycline may be of use for the augmentation of noradrenergic antidepressant drugs [27].
Posted by poser938 on January 4, 2013, at 0:27:24
In reply to Re: More evidence of inflammation and depression. » poser938, posted by SLS on January 3, 2013, at 22:59:03
Very interesting. I like what it has been shown to do with dopamine. I am definitely going to ask my psychiatrist about minocycline Monday.
I may be going to the Vanderbilt research hospital soon. I'm not quite sure what to expect from staying in this hospital, but I'm excited. I figured all along that I needed a place like this.
Posted by SLS on January 4, 2013, at 0:40:33
In reply to Re: More evidence of inflammation and depression., posted by poser938 on January 4, 2013, at 0:27:24
> Very interesting. I like what it has been shown to do with dopamine. I am definitely going to ask my psychiatrist about minocycline Monday.
> I may be going to the Vanderbilt research hospital soon. I'm not quite sure what to expect from staying in this hospital, but I'm excited. I figured all along that I needed a place like this.
Good luck at Vanderbilt. I hope you can post updates as to how you are doing.
- Scott
Posted by SLS on January 4, 2013, at 9:44:19
In reply to Re: More evidence of inflammation and depression. » poser938, posted by SLS on January 3, 2013, at 22:59:03
Minocycline protects neurons from dying by suppressing toxic events. Cell death triggers immune resposes that include brain inflammation. One mechanism by which minocycline protects these cells is the suppression of glutamatergic hyperexcitability and Ca2+ ion influx. Minocycline also protects cells by reducing the formation of damaging oxidative free radicals inside the cell. These species can wreak havoc with events inside the cell nucleus. Minocycline thus reduces the damage to cell viability by suppressing glutamate overacitiviy.
Of particular interest to me is the ability of minocycline to inhibit the release of glutamate. I believe that this effect works synergistically with the antiglutamatergic effects of Lamictal. Combining these two drugs together might prove especially effective in the treatment of depression, particularly when there is a bipolar diathesis.
Unlike the dogma promoted in decades gone by that supported the notion that affective disorders were not organic, we now realize that mood illnesses are degenerative. Cells die. Connections die. Fortunately, when one responds well to drug treatment, many of these cells recover while new cells are being born. The hippocampus is a brain structure known to facilitate memory and modulate mood. It shrinks (atrophy?) with depression. The recovery of this structure is easily measured when antidepressants are administered.
Minocycline reminds me of lithium. It has many, many different biological properties that seem to converge to produce its therapeutic effects.
I spent some time trying to excise passages from the following text in various ways, but I found that I kept deleting important information. So, I kept most of it and posted it here. It is long and somewhat technical, but I skipped the methods and results sections and their nomenclature jibberish. Just skim and skip to the good parts. I still must skim long texts due to my impaired concentration. I am not very happy with how long it is taking me to regain my abilility to read with my current treatment.
- Scott
--------------------------------------------------
Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca2+ signalling in hippocampal neurons
José Carlos González,1,2 Javier Egea,1,2 María del Carmen Godino,3 Francisco J. Fernandez-Gomez,5
José Sánchez-Prieto,3 Luís Gandía,1,2 Antonio G. García,1,2,4 Joaquín Jordán5 and Jesús M. Hernández-Guijo1,2 1Instituto Teófilo Hernando, and
2Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, E-28029 Madrid, Spain
3Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain
4Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
5Grupo de Neurofarmacología, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha y Centro Regional de Investigaciones Biomédicas, Albacete, SpainKeywords: glutamate release, synaptic transmission, tetracycline
Abstract
The mechanism of the neuroprotective action of the tetracycline antibiotic minocycline against various neuron insults is controversial.
In an attempt to clarify this mechanism, we have studied here its effects on various electrophysiological parameters, Ca2+ signalling,
and glutamate release, in primary cultures of rat hippocampal neurons, and in synaptosomes. Spontaneous excitatory postsynaptic
currents and action potential firing were drastically decreased by minocycline at concentrations known to afford neuroprotection. The
drug also blocked whole-cell inward Na+ currents (INa) by 20%, and the whole-cell Ca2+ current (ICa) by about 30%. Minocycline
inhibited glutamate-evoked elevation of the cytosolic Ca2+ concentration ([Ca2+]c) by nearly 40%, and K+-evoked glutamate release
from synaptosomes by 63%. Minocycline also depressed the frequency and amplitude of spontaneous excitatory postsynaptic
currents, but did not affect the whole-cell inward current elicited by c-aminobutyric acid or glutamate. This pharmacological profile
suggests that the neuroprotective effects of minocycline might be associated with the mitigation of neuronal excitability, glutamate
release, and Ca2+ overloading.Discussion
The main aim of this study was to obtain better knowledge about the mechanism responsible for the neuroprotective effects of minocycline on glutamate-induced cytotoxicity. We used hippocampal neurons in culture, which are formed by approximately 80% of glutamatergic neurons (pyramidal cells) vs. 20% of GABAergic neurons (interneu- rons and granular cells); similar rates has been described in cortex primary culture(Millán et al.,2003). As shown in Fig.1, the glutamate treatment produced a significant decrease in cell viability.
To determine the effect of minocycline on glutamate-induced toxicity, hippocampal neurons were pretreated with a wide range of concen- trations (10-150 lm), which were observed to afford cytoprotection to the neuronal hippocampal culture in a concentration-dependent manner. We found in this study that neuroprotectant concentrations of minocycline against brain ischaemia (Yrjanheikki et al., 1999), excitotoxicity (Tikka et al., 2001), spinal cord injury (Stirling et al., 2004) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (He et al., 2001) depressed synaptic transmission in cultured hippocampal neurons. This depression is explained by reduction of sEPSCs, recorded in the presence of the GABAA receptor blocker bicuculline. The current frequency, the amplitude and the area of individual events are reduced approximately by 50% (Fig. 2). We demonstrate how minocycline could contribute to decrease neuronal excitability, not only by blocking depolarizing ionic channels, but also by an additional direct modulation of glutamate release. Hence, minocycline was probably reducing glutamate release, a mechanism that was directly tested in cortical synaptosomes, using high K+ as a depolarizing stimulus (Fig. 10). A postsynaptic effect explaining sEPSC depression is discarded, considering that minocycline did not affect either glutamate- or GABA-induced inward currents (Fig. 11). The presynaptic action of minocycline was corroborated by recording the spontaneous AP firing. Thus, the drug reduced the frequency of spontaneous APs recorded in current-clamped hippo- campal neurons (Fig. 3). Furthermore, the drug diminished the amplitude and the frequency of AP trains elicited by current injection, leading to a late suppression of cell firing (Fig. 4). The reduction of AP frequency is probably due to an increase in the after-hyperpolarisation duration, a slight increment of baseline, and a drastic increment in AP decay time. These changes augment the refractory period, and the subsequent decrease, of AP frequency. This effect of minocycline on AP generation and propagation may be explained by a combination of effects on various ion channel currents. For instance, minocycline reduced INa by 20% (Fig. 5), ICa by 30% (Fig. 8), and IKCa by 50% (Fig. 7). We measured the contribution of Ca2+-channels and voltage- dependent K+-channels to the total outward K+ current at potentials occurring during an AP, i.e. from )20 mV to +30 mV. This implies that over 22% of the K+ current measured in the first millisecond of a depolarizing step is activated by Ca2+ influx. Thus, blockade by minocycline of ICa (Fig. 8) may explain its blocking effect on IKCa (Fig. 7). Additionally, the possibility of Ca2+-dependent K+ current suppression exerted by a direct action of minocycline on Ca2+- dependent K+-channels is completely excluded by the similar IC50 obtained in both experimental approaches, blockade of ICa and IKCa. The Ca2+ currents were recorded in 10 mm external Ca2+ however, the use of high Ca2+ only shifted I / V 10 mV to the right (the control and the blockade curve). We performed some control experiments, recording the blockade exerted by minocycline at two potentials (0 and +10 mV) in comparison to 2 and 10 mm Ca2+, and no difference was detected. The extracellular concentration of Ca2+ did not affect the relative blockade exerted by minocycline. The blockade obtained in 10 mm Ca2+ at +10 mV is the same as that observed at 0 mV in 2 mm Ca2+. It was interesting that blockade was higher at test potentials (i.e. 0 mV), where ICa is known to be maximal; this corroborates the well- known observation that Ca2+ entering through voltage-dependent Ca2+-channels rapidly activates small- and large-conductance Ca2+- dependent K+-channels. As these channels control the post-hyperpo- larization phase of the AP and hence AP firing frequency [see Stocker (2004) for a review], the halving by minocycline of IKCa (Fig. 7) may explain the reduction of AP frequency and even the suppression of AP firing (Figs 3 and 4). The increment in the intracellular concentration of Ca2+ during neuronal ischaemia evoked by glutamate-derived hyperexcitability plays a particularly important role in the neurotoxic cascade resulting in acute neuronal cell death. Additionally, a reduction in the Ca2+ influx leads first to a decrement in cytosolic Ca2+ level to initiate the exocytotic process, and glutamate release, and second, to a decrement in the Ca2+-induced Ca2+ release responsible for maintenance of
Minocycline decreases neuronal excitability2493
Fig. 11. Effects of minocycline on glutamate- or c-aminobutyric acid (GABA)-evoked currents. (A) Hippocampal neurons in culture were perfused with Tyrode control solution and stimulated with 300 lm glutamate for 100 ms at 30-s intervals in the absence and presence of minocycline (added 2 min before). The histogram represents the average data for glutamate-induced responses in both conditions. (B) A hippocampal neuron perfused with Tyrode solution was stimulated with 100 lm GABA for 100 ms at 30-s intervals before (control trace) and during minocycline perfusion. The histogram represents the average data for GABA-induced responses in control conditions and in the presence of minocycline (added 2 min before). For each cell, the response in the presence of minocycline was calculated as a percentage of the response in control conditions (100%). Data are means ± SEM of number of neurons tested (indicated in parentheses). No statistical differences were found
Fig. 10. Minocycline reduces glutamate release in a concentration-dependent manner in cerebrocortical nerve terminals. (A) The release of glutamate evoked by 30 mm KCl in the presence of 1.33 mm Ca2+ or 5 mm EGTA was determined in the presence and absence of minocycline (10, 50 and 100 lm) added 100 s before depolarization. Note the lack of effect on external Ca2+- independent glutamate release (EGTA traces). Traces are the means of three to five experiments using two synaptosome preparations. (B) Averaged data of glutamate release in the absence (control) and the presence of minocycline. Data are means ± SEM of the number of cells shown in parentheses. **P < 0.01, with respect to control. (C) Minocycline fails to affect ionomy- cin-induced glutamate release. The lower trace shows the basal spontaneous release obtained. Glutamate release was induced by 6 lm ionomycin in the absence (control) or the presence of minocycline (100 lm), added 100 s before. Traces are the means of three to five experiments using two synaptosome preparations between the different experimental groups.
Vesicular transport for neurotransmitter release. The partial blockades exerted by minocycline of INa and ICa were translated into a 30-40% decrement of [Ca2+]c elevations elicited by glutamate (Fig. 9). This may explain the 60% blockade of K+-evoked glutamate release (Fig. 10). The K+-evoked release is not affected by either Na+-channel or K+-channel blockers, but is sensitive to inhibition by Ca2+-channel blockers (Millán et al., 2002). Nevertheless, the possibility of direct interference of minocycline with the exocytotic machinery release itself, downstream of Ca2+ entry, was excluded by the observation that minocycline did not affect the ionomycin-induced release of glutamate. Thus, these combined effects of minocycline may consid- erably reduce the neuronal Ca2+ overload evoked by excess glutamate stimulation of N-methyl-d-aspartate receptors, occurring during brain ischaemic insults (Siesjo et al., 1995). Observation of the effects of minocycline with the different experimental approaches suggested that 30 lm was the threshold concentration to exert all these effects. The effectiveness of minocycline achieved with the same concentration range (see similar calculated IC50) suggests that the blockade exerted on cytosolic Ca2+ elevation, and neurotransmitter release, which eventually led to a decrement in neuronal excitability, are mainly evoked by a direct blockade of voltage-dependent Ca2+-channels, without discounting a small contribution of other mechanisms, such as Na+-channel blockade. We have not considered an effect of minocycline on the different cell types and the possibility that pooling data from all cells may mask cell-type-specific effects because: (i) during the experiment performed, the hippocampal neurons recorded showed a pyramidal-like shape; (ii) the homogeneous effect recorded in every experimental approach, as shown by the low SEM, indicates a normal distribution effect, which excludes the possibility that different effects exerted by minocycline could be associated with different cell populations; and (iii) to prevent variations in the development of the primary culture, we employed 11-15-day-old neurons. Minocycline exhibits neuroprotective effects against neuronal damage in animal models of focal and global brain ischaemia (Yrjanheikki et al., 1999; Wang et al., 2003), Huntingtons disease (Chen et al., 2000; Wang et al., 2003), amyotrophic lateral sclerosis (Zhu et al., 2002), Alzheimers disease (Hunter et al., 2004), and Parkinsons disease (He et al., 2001). In particular, during and after ischaemic insults, there is consensus that excess glutamate release and impairment of glutamate sequestration by astrocytes might be the cause of exacerbated neurotoxicity and neuronal death [see Block et al. (2007) for a review]. In fact, therapeutic targets to mitigate such neurotoxicity include Ca2+-channel blockers to reduce excess gluta- mate release (Gribkoff & Winquist, 2005) or glutamate receptor blockers (García de Arriba et al., 2006). The cell viability experiments in which minocycline exerted a important neuroprotective effect, in contrast to the smaller effect evoked by other compounds, such as tetracycline, are in accordance with other studies showing that minocycline and doxycycline markedly reduce the size of infarction in both focal and global transient ischaemia in the adult rat (Clark et al., 1994; Yrjanheikki et al., 1999; Xu et al., 2004); by contrast, tetracycline, which is less able to cross the blood-brain barrier to enter the central nervous system, is not neuroprotective at the same doses (Yrjanheikki et al., 1998). The data available on the mechanism responsible for the neuropro- tective actions of minocycline are scarce and controversial (Jordán et al., 2007). Several reports attribute the minocycline neuroprotective effects to various intracellular signalling pathways, including antiox- idant systems (Kraus et al., 2005), nitric oxide synthase (Sadowski & Steinmeyer, 2001) and blockade of inflammatory responses [see Stirling et al. (2005) for a review]. Our results, however, strongly suggest that minocycline acts at an earlier plasmalemmal step by limiting glutamate release and the ensuing [Ca2+]c elevation in target neurons. Minocycline may prevent the activation of this Ca2+- dependent intracellular pathway, thus preventing neuronal death. The regulatory mechanism exerted by minocycline on Ca2+ entry and membrane potential leads to down-modulation of synaptic transmis- sion. This decrement in neuronal excitability, together with the marked decrement in glutamate release, may explain the cytoprotective properties of this drug. On the other hand, downregulation of the neuronal network activity may prevent microglial overactivation, with a favourable effect on neurodegenerative diseases. In fact, minocycline has been demonstrated to inhibit microglial activation (Yrjanheikki et al., 1999; He et al., 2001; Tikka et al., 2001), a finding that is in accordance with its neuroprotective effects in animal models of neurodegenerative diseases or ischaemia (Yrjanheikki et al., 1999; Chen et al., 2000; Zhu et al., 2002; Wang et al., 2003; Hunter et al., 2004). In conclusion, our observation that minocycline mitigates the excitability of hippocampal neurons by direct blocking of ionic channels involved in the generation and propagation of APs, and depresses glutamate release and Ca2+ overloading by the partial blockade exerted on voltage-dependent Ca2+-channels, may explain the well-studied neuroprotective properties of this tetracycline derivative in various in vitro and in vivo models of neurotoxicity.
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Posted by jono_in_adelaide on January 4, 2013, at 15:46:43
In reply to Re: More evidence of inflammation and depression., posted by SLS on January 4, 2013, at 9:44:19
Minocycline is apparently the new black
Posted by larryhoover on January 6, 2013, at 20:11:31
In reply to More evidence of inflammation and depression., posted by SLS on January 2, 2013, at 7:54:16
Hey, Scott. I hope you don't mind that I drop a few ideas into this thread. I've been doing a lot of literature research, starting with an earlier thread about inflammation and diet, and I've come to some interesting conclusions. Or, at least, some interesting questions, worthy of further investigation.
The association between inflammation and mental illness has been recognized for about a century. What's interesting to me is that dietary control of inflammation, with respect to mental illness, has generally only been applied to epilepsy. And yet, anti-epileptic drugs have come to be a considerable component of the arsenal applied to bipolar and related mood disorders.
A high-fat, low-carb diet has been the fall-back treatment for epilepsy for a very long time. And it is now in consideration for treatment in other disorders, including Alzheimer's, Parkinson's, and others. The reason is that it reduces brain inflammation, and boosts mitochondrial function. I'll give you a few full-text
links to consider:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649682/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2367001/
The great thing about PMC is that it provides direct access to supporting references at each point in the article where they're referenced (shown to the right of the text).And, just for a supporting role, you can consider this abstract:
http://www.ncbi.nlm.nih.gov/pubmed/17663642You'll see that antioxidant status is improved under a high-fat, low-carb diet. For the record, a ketogenic diet is distinct from the ketoacidosis caused by uncontrolled diabetes. We're talking about the middle ground, here. When toxic carb intake is controlled, fat metabolism is more than capable of providing all the energy your body requires, and can do so in a safer fashion. In fact, I'd say that fat metabolism is the default energy source, and carb metabolism is the emergency one.
I'm at the airport, waiting for a flight, and I don't have time to give a detailed analysis of the subject, but I have discovered that there is a significant confound in any study into what are considered to be the diseases of western civilization, i.e. diabetes, obesity, cancer, hypertension, and senility. You may have trouble accepting just what that confound might be, but it is electric light.
My investigation began after I saw a TV program which showed that a simple machinery malfunction could induce obesity and inflammation in laboratory rats. The animals were to have been in a 12-hour cycle of light and dark, but the light controller failed, and the animals were exposed to 24-hour light. It took some time for the defect to be discovered, as the scientists themselves were absent from the lab during the period that was supposed to be dark, but in the meantime, the rats became obese and showed significantly enhanced inflammatory responses, despite the fact that all other variables were controlled. Light alone had made them fat and inflammatory.
If you look into the literature (Pubmed), you'll find that human experience matches that of the rats. In fact, it has always been a question raised in ecological monitoring of human health, how is it that adverse health effects associated with "diseases of western civilization" seem to precede changes in diet. Traditionally, consumption of refined carbohydrates, or intake of meat, has been blamed for these health outcomes (listed above), but the timing was inconsistent with dietary shifts; adverse health effects tended to precede dietary changes. Restrospective analysis has shown a near perfect correlation with the advent of electric lighting. Lights came first, diet changed after.
Further research has determined that blue light is the probable culprit. Blue light, sensed by the suprachiasmatic nucleas (SCN), and expressed in the reduced pineal secretion of melatonin, is the probable mechanism for this effect.
If you wish to research this further on Pubmed, I'll provide you with some keyword searches. I just don't have time, now at the airport, to give the needed references.
Some keywords/phrases are: circadian disruption, sometimes referenced as CD. This is a broad term, encompassing many subcidiary terms, which I will try to encompass more specifically. "night shift" covers a specific group of human workers, often a term applied to cancer investigations. (Hormone regulated cancers, i.e. breast, prostate, and ovarian, are directly caused by shift work.) The key variable appears to be decreased melatonin secretion, suppressed by blue light exposure after the sun goes down. And blue light is released by electric lights of all types, but not by candles, oil lamps, or open flame.
There are other phrases that pop up (light at night, or LAN). "Shift work", as a variant on night shift. In any case, combine these keywords/phrases with cancer, inflammation, obesity, hypertension, and be prepared to be amazed.
I'm concerned that posters here are trying to simplify an amazingly complex and confounded system down to single variables to manipulate for improvement of mental health. I don't think that is possible. You have to look at the package.
Earlier, I believe I provided compelling evidence that carbohydrate intake was the inflammatory (and obesigenic) variable in our diets. Carb restriction was the simple solution. But what about blue light exposure after the sun goes down? Surely, that is a variable of concern. And how do these variables play into depression? I don't know, but I'll tell you about my experience.
Once I made restorative sleep the primary variable in my own treatment protocol, I began to recover. Even one day of poor sleep has a significantly adverse effect on me. So, it is number one in my world. And, as part of that treatment protocol, I have been supplementing with melatonin. What I have recently discovered through Pubmed has provided me with extraordinary support. I always knew that melatonin was probably the most powerful free-radical scavenger and antioxidant produced by the body, but I hadn't realized how important it was in other aspects of health. Combine melatonin and mitochondria in a Pubmed search, and see what you get. Look at melatonin and heart disease, or obesity, or diabetes. Maybe blue-light mediated suppression of melatonin secretion by the pineal gland is the cause (yes, cause) of all of these adverse health effects, including depression.
All I know is, I have been using melatonin as a sleep aid for six years or more, and over that period, I have been doing better. I am not well (in my historical sense of self), but I am very much better. I think I got lucky, picking this supplement. But I now see why it might have been an amazingly beneficial choice. BTW, it apparently also treats ulcers, as an oral supplement. Who knew?
Blimey, the plane is boarding. Please, expand your search for health-limiting variables. Put together a package of behavioral changes. And optimize what you have in your life. It ain't all about meds. I won't ever be the man I was before I took ill, but I can be the man possible thereafter. If, and only if, I control the variables that I can.
Lar
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