![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 16 to 40 of 44. Go back in thread:
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
Posted by SLS on January 6, 2013, at 21:35:15
In reply to Re: More evidence of inflammation and depression., posted by larryhoover on January 6, 2013, at 20:11:31
I eat a diet high in carbohydrates, mostly because I still lack the energy and motivation to cook. Bread and cereal are cheap and easy. I definitely crave them. Abilify doesn't help. I have begun to change my behaviors, though, but I have trouble changing them all at once. Today was fresh broccoli day. For me, this is a significant change.
I feel that you hit the target with much of what you have written over these last few weeks. You have changed the way I think about diet. I appreciate the information that you present and your insights. It makes sense to eat and exercise your way to good health; as good as one's biology will allow.
When I was in my 20s, I changed my diet to be rich in protein and vegetables. I stayed away from sugars and starches. I exercised regularly. I remained very ill despite all of this. If I were to replicate these behaviors, I imagine I would feel better in a way an otherwise healthy person would feel were they to make similar changes. However, my experiences lead me to believe that diet is not the culprit in my illness. I have even looked at food allergy and have performed rotation diets.
Melatonin makes my depression decidedly worse. I took it at night, though. Some people need to take it in the early afternoon in order for their sleep to improve at night. Prazosin has helped me sleep along with reducing depression. My sleep had been very choppy previously. That said, my current sleep hygiene is not optimal. I need to make some changes.
Too many bagels.
- Scott
Posted by Phil on January 6, 2013, at 21:42:43
In reply to Re: More evidence of inflammation and depression. » larryhoover, posted by SLS on January 6, 2013, at 21:35:15
I buy frozen vegetables sometimes throw them in the microwave and eat a few Popsicles while they nuke.
Posted by SLS on January 6, 2013, at 21:46:06
In reply to Re: More evidence of inflammation and depression. » SLS, posted by Phil on January 6, 2013, at 21:42:43
> I buy frozen vegetables sometimes throw them in the microwave and eat a few Popsicles while they nuke.
:-)
- Scott
Posted by larryhoover on January 7, 2013, at 5:04:43
In reply to Re: More evidence of inflammation and depression. » larryhoover, posted by SLS on January 6, 2013, at 21:35:15
> I eat a diet high in carbohydrates, mostly because I still lack the energy and motivation to cook. Bread and cereal are cheap and easy. I definitely crave them. Abilify doesn't help. I have begun to change my behaviors, though, but I have trouble changing them all at once. Today was fresh broccoli day. For me, this is a significant change.
That craving thing goes away pretty quickly, if you drop carb intake into the 10-15% of calories range. And I'm not anal about my diet, in this regard. Any change I make is an improvement on what I had been doing.
I totally get the convenience factor of refined carbs, though. I seem to always have way too much food in my pantry. After I looked around the other day, I realized just how much of it was high-carb. I think I'm going to feel guilty if I take a bunch of that stuff to the food bank....but I guess it's better to have a meal than to go hungry. Been there.
> I feel that you hit the target with much of what you have written over these last few weeks. You have changed the way I think about diet. I appreciate the information that you present and your insights. It makes sense to eat and exercise your way to good health; as good as one's biology will allow.
Thank you, Scott. Glad to be seen in that light.
> When I was in my 20s, I changed my diet to be rich in protein and vegetables. I stayed away from sugars and starches. I exercised regularly. I remained very ill despite all of this. If I were to replicate these behaviors, I imagine I would feel better in a way an otherwise healthy person would feel were they to make similar changes. However, my experiences lead me to believe that diet is not the culprit in my illness. I have even looked at food allergy and have performed rotation diets.
My way of thinking is that I may not be able to fix my brain, but I may as well have it in the healthiest environment that I can produce. I admit quite readily that I was surprised to learn that standard nutritional dogma vis a vis fat intake was actually false. Quite opposite to the truth, in fact. And this whole set of questions in respect of inflammation has inspired me to investigate a host of other variables in my life.
It may be a simple coincidence, but I make a habit of taking antioxidant supplements daily, and I'm doing rather well. Perhaps those have been supportive of my better functioning. I could never have said that I knew they were helping me, though. The effects are too subtle for that sort of conclusion.
> Melatonin makes my depression decidedly worse. I took it at night, though. Some people need to take it in the early afternoon in order for their sleep to improve at night. Prazosin has helped me sleep along with reducing depression. My sleep had been very choppy previously. That said, my current sleep hygiene is not optimal. I need to make some changes.Interesting, your response to melatonin. One thing to consider is that commonly available doses range by a factor of 20, from a low of 0.30 mg, up to a high of 6 mg. There may be others beyond those extremes, I don't know. My own sweet spot lies in around 0.50-0.60 mg/night. And as melatonin is a hormone, you have to be careful to not take too much. If you do, it could actually lessen sleep quality. It's best, therefore, to titrate the dose slowly, until you get a sense of how it affects you. I have no idea if that will prevent your adverse reaction, though.
The only meds I take are sleep related: temazepam 30 mg, and trimipramine 25 mg. I did a slow taper of the benzo a couple of years ago, and waited six weeks at zero dose, but my sleep architecture just did not permit restorative sleep. So, I started taking it again, and it still works. For me, Restoril is just that.
> Too many bagels.
>
>
> - ScottWell, you can address that, one bagel at a time.
Off to the airport for another try to get out of here.
Best,
Lar
Posted by adela on January 14, 2013, at 13:14:47
In reply to Re: More evidence of inflammation and depression., posted by larryhoover on January 6, 2013, at 20:11:31
Hi Lars, I read with interest your suppositions about exposure to too much light, blue light and too many carbs. I was wondering if those who live in the Northern hemisphere suffer from the type of depression those who live in more or less a 4 season climate do. When peoples of the norther hemisphere live with daylight really 24/7 in their summer, do they experience or develope depression?
I do know that depression and the ups of bi polar cause sleepless nights and the overall disruption of a healthy pattern of sleep and this disruption exacerbates symptoms. So the fact that you have tried melatonin and have seen positive results for you makes me want to look it its use to help create and establish a good sleep cycle. There are so many warning about being on melatonin over a ong period of time but you say you have been on it for 6 year with no issues. Have you ever had a full physical with blood work, liver functions, etc. done to see if there is no cause for concern for the extended use of melatonin? IS the light of a computer screen considered blue light? Thank you for a good post.
Posted by larryhoover on January 18, 2013, at 20:23:52
In reply to Re: More evidence of inflammation and depression., posted by adela on January 14, 2013, at 13:14:47
> Hi Lars, I read with interest your suppositions about exposure to too much light, blue light and too many carbs. I was wondering if those who live in the Northern hemisphere suffer from the type of depression those who live in more or less a 4 season climate do. When peoples of the norther hemisphere live with daylight really 24/7 in their summer, do they experience or develope depression?
The contrary situation, caused by decreased sunlight in winter, most certainly causes depression. "Cabin fever" is a slang term for the outcome. Seasonal affective disorder has long been associated with latitude. Lights with a strong blue wavelength spectrum are often used to treat seasonal affective disorder.
There is also a form of seasonal affective disorder that leads to depression in summer. The causative mechanism is not understood.
> I do know that depression and the ups of bi polar cause sleepless nights and the overall disruption of a healthy pattern of sleep and this disruption exacerbates symptoms. So the fact that you have tried melatonin and have seen positive results for you makes me want to look it its use to help create and establish a good sleep cycle. There are so many warning about being on melatonin over a ong period of time but you say you have been on it for 6 year with no issues.
I am absolutely unaware of adverse effects of oral melatonin supplementation. In fact, I just spent over an hour searching the medical literature for cautions with respect to oral melatonin. Rather than discovering adverse effects, I discovered clear evidence that melatonin reduces tardive dyskinesia associated with antipsychotics, improves response to chemotherapy in breast cancer, and reduces effects of stomach ulcers. My keyword search was adverse effects, and I found benefits.
There is a caution I would bring forward, however. Melatonin is a hormone, and like any hormone, it has in inverted U-shaped dose/response curve. What that means is that there is a significantly positive dose-reponse effect at lower doses, but at some point, the response reaches a plateau, i.e. further increases in dose have no positive effect. If the dose is increased even further, the response falls back to zero. What that means is that the body no longer recognizes the hormone. Just as you can develop insulin resistance, you can certainly develop (oral) melatonin resistance. The key is to determine your own response to oral melatonin supplements. Based on discussions here, individual dose/response to oral melatonin varies by at least a factor of ten.
That is why I have long advocated titrating up from a low dose of melatonin (say, 0.50 mg), in small increments, until you find an effective dose. Nothing will be gained from increasing the dose beyond that point, so if you find something that works, stick with it. That level has been reported at anywhere between 0.6 and 10 mg.
Melatonin is one of the most powerful antioxidants your body can produce. But, if blue light impinging on your supra-chiasmatic nucleus (SCN) blocks melatonin release from your pineal gland, your only option is to supplement that hormone.
Your questions have caused me to look closer at the subject, and I appreciate that. It may be true that sustained or continuous release preparations of melatonin are optimal, due to the short half-life of melatonin. I'm going to try those formats.
> Have you ever had a full physical with blood work, liver functions, etc. done to see if there is no cause for concern for the extended use of melatonin?
I have no health concerns, and I am routinely monitored for same. Melatonin is an extraordinary antioxidant, and I struggle to understand the basis for your concern.
> IS the light of a computer screen considered blue light?
Yes. However, if you are unwilling, or unable, to modify your exposure to electric light, I believe the solution is to supplement with melatonin.
> Thank you for a good post.
It has been a pleasure.
Lar
Posted by larryhoover on January 18, 2013, at 20:49:27
In reply to Re: More evidence of inflammation and depression. » larryhoover, posted by SLS on January 6, 2013, at 21:35:15
> I eat a diet high in carbohydrates, mostly because I still lack the energy and motivation to cook. Bread and cereal are cheap and easy. I definitely crave them. Abilify doesn't help.
I totally get that, Scott, my friend. Carbs are easy because they store so well, and they are addictive, too.
> I have begun to change my behaviors, though, but I have trouble changing them all at once. Today was fresh broccoli day. For me, this is a significant change.
That it was a change is indeed significant. There are no rules to be met, no boundary conditions which lead to success. Any change in the right direction is better than the alternative.
> I feel that you hit the target with much of what you have written over these last few weeks. You have changed the way I think about diet.
Thank you, Scott. I am grateful for your recognition of my efforts. Before now, I just hadn't realized the extent to which we had been decieved.
> I appreciate the information that you present and your insights. It makes sense to eat and exercise your way to good health; as good as one's biology will allow.
There is no right dietary answer, but it most certainly makes sense to find your own right answer.
> When I was in my 20s, I changed my diet to be rich in protein and vegetables. I stayed away from sugars and starches. I exercised regularly. I remained very ill despite all of this.
I'm sorry to hear that, Scott. I don't know, we're all so very unique. Here's an interesting study, that followed up a 12-week weight-loss induction diet with a cross-over study of low-carb, low-glycemic, and low-fat diets. The low-carb was the victor, but it did reveal an increase in 24-hour cortisol and C-reactive protein. I've not seen those responses in other studies, but it may be due to the short duration of the dietary interventions.
http://jama.jamanetwork.com/article.aspx?articleid=1199154
Really nice tables in this one.
> If I were to replicate these behaviors, I imagine I would feel better in a way an otherwise healthy person would feel were they to make similar changes. However, my experiences lead me to believe that diet is not the culprit in my illness. I have even looked at food allergy and have performed rotation diets.My answer is not evidence that it will be your answer. I get it. But carbs are toxic. The evidence is overwhelming.
> Melatonin makes my depression decidedly worse. I took it at night, though. Some people need to take it in the early afternoon in order for their sleep to improve at night.
I was just looking at that, based on adela's questions. There are a number of timed-release, or continual release melatonin formulations. And they're quite cheap (based on a search of iherb).
> Prazosin has helped me sleep along with reducing depression. My sleep had been very choppy previously. That said, my current sleep hygiene is not optimal. I need to make some changes.
Prazosin? I am not asking for a reveal here, but my literature search associated it with PTSD. I have that, in spades, and melatonin and temazepam work for me.
> Too many bagels.
>
>
> - ScottHave you ever had a Montreal bagel? I'm told they are better than New York bagels, which is saying a lot.
Best,
Lar
Posted by Phillipa on January 18, 2013, at 21:22:49
In reply to Re: More evidence of inflammation and depression. » SLS, posted by larryhoover on January 18, 2013, at 20:49:27
Lar does Butter Tart ring a bell? Phillipa
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