Potential treatment for SPMS and/or PPMS

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Potential treatment for SPMS and/or PPMS

Postby Anonymoose » Fri Mar 15, 2013 11:40 am

Combination of Dizocilpine (NMDA receptor blocker) and Nimodipine (ca-channel blocker, maybe nifedipine too?) may help SPMS and PPMS via neuroprotection, reduced spasticity, and potentially increased cerebral perfusion if vasospasms are a factor.

dizocilpine http://en.wikipedia.org/wiki/Dizocilpine
nimodipine http://en.wikipedia.org/wiki/Nimodipine (do NOT mix with zanaflex regimens-f22/topic898-60.html#p8952)

Neuroprotection:

Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis 2008 Full Text
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2267014/
Our data demonstrate the neuroprotective effect of treatment with a fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of progressive MS and other neurodegenerative diseases.

http://www.ncbi.nlm.nih.gov/pubmed/8819136
In vivo protection against NMDA-induced neurodegeneration by MK-801 and nimodipine: combined therapy and temporal course of protection.
Stuiver BT, Douma BR, Bakker R, Nyakas C, Luiten PG.
Source
Department of Animal Physiology, University of Groningen, Haren, The Netherlands.
Abstract
Neuroprotection against excitotoxicity by a combined therapy with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the L-type Ca2+ channel blocker nimodipine was examined using an in vivo rat model of NMDA-induced neurodegeneration. Attention was focused on the neuroprotective potential of this combined drug treatment before and after NMDA-exposure. NMDA was unilaterally injected in the magnocellular nucleus basalis (MBN). Neuronal damage was assessed 12 days after the NMDA-injection by measuring the reduction of cholinergic cortical fibres that originate from the MBN neurons. In controls that received no drug treatment, NMDA-exposure damaged MBN neurons such that 66% of the cholinergic terminals were lost in the ipsilateral parietal cortex. Pretreatment with a nimodipine diet (860 ppm) combined with application of MK-801 (5 mg/kg i.p.) before NMDA-exposure reduced fibre loss by 89% thereby providing a near complete neuroprotection. Combined therapy of MK-801 (5 mg/kg i.p.) and nimodipine (15 mg/kg i.p.) 8 min after NMDA-infusion reduced neuronal injury by 82%, while the same combination given 2 h after the excitotoxic treatment still yielded a 66% protection against neurotoxic damage invoked by NMDA. In conclusion, the present data show that a dual blockade of NMDA-channels and voltage-dependent calcium channels (VDCC's) up to 2 h after NMDA-exposure is able to provide a significant protection against NMDA-neurotoxicity.


A JackD post about calcium channel blockers
general-discussion-f1/topic10099-15.html#p91543

Spasticity:
Ca-channel blockers reduce neuronal excitability.
http://www.medmerits.com/index.php/arti ... sticity/P5
The neuropathophysiologic processes involved in spasticity are complex and not fully understood, but there is a widely accepted hypothesis that spasticity depends on hyperexcitability of spinal alpha motor neurons, which is due to the interruption of descending modulatory influences carried by the corticospinal, vestibulospinal, and reticulospinal tracts and other possible tracts (Filloux 1996). Ia afferent fibers provide segmental input from muscle spindles to alpha motor neuron pools. They synapse on segmental inhibitory interneurons that then inhibit alpha motor neurons innervating antagonist muscles in the Ia reciprocal inhibition pathway. Ib afferents inhibit alpha motor neurons by way of the Golgi tendon organs via the Ib inhibitory interneuron in another pathway known as nonreciprocal inhibition (Young 1994; Filloux 1996). Increased excitation of these afferents does not seem to be the cause of spasticity. Instead, evidence supports that reduced reciprocal inhibition of antagonist motor neuron pools by Ia afferents, decreased presynaptic inhibition of Ia afferents, and decreased nonreciprocal inhibition by Ib terminals are all possible pathophysiologic mechanisms of spasticity (Young 1994). The pathophysiology of traumatic brain injury involves a complex combination of forces that has been a subject of substantial debate (Drew and Drew 2004). On occasion, autonomic dysreflexia may occur after an intramuscular injection, although this is relatively rare (Selcuk et al 2004). In some patients, autonomic dysreflexia may occur even if the level of spinal injury is below T6 (Blackmer 2003; Krassioukov et al 2003). The use of antihypertensive pharmacologic agents in treating spasticity is unclear because randomized trials have not been performed. Nifedipine has been used in a bit-and-swallow technique; more recently, captopril also has been found to be of benefit (Esmail et al 2002).


Increased cerebral perfusion:
Everything seems related to vasospasm. Since we don't know this is a factor, not bogging thread down with studies.

Random benefits:

Nimodipine and nifedipine enhance transmission at the Schaffer collateral CA1 pyramidal neuron synapse (might help w/adrenal issues)
http://link.springer.com/article/10.100 ... 78?LI=true

Relief from post-O(rgasm) headaches
http://onlinelibrary.wiley.com/doi/10.1 ... ated=false
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Re: Potential treatment for SPMS and/or PPMS

Postby Anonymoose » Fri Mar 15, 2013 12:58 pm

More on NMDA
Image
They left NMDA out of the picture. I believe it belongs between glutamate release and resulting "stuff."

http://www.scielo.br/scielo.php?pid=S01 ... ci_arttext
It is well known that one of the main effects of the stress response is the release of large quantities of excitatory amino acids, such as aspartate and glutamate, in different brain areas, an effect occurring rapidly after the onset of stress (20 min to 2 h) (3).

Released glutamate can bind to different receptors; the main one being the N-methyl-D-aspartate (NMDA) subtype, whose activation causes the mobilization of free cytosolic calcium. Excess in the intracellular calcium concentration over-activates certain calcium-dependent enzymes resulting in the generation of oxygen radicals, protein misfolding and cytoskeletal damage (14), constituting the process known as excitotoxicity.

Trying to go further in the sequence of events initiated by stress exposure, we also investigated the possible influence of glutamate in the release of TNF-α by blocking the NMDA glutamate receptor with the specific non-competitive compound MK-801 (dizocilpine). Interestingly, NMDA blockade not only decreases stress-induced activity and expression of TACE, but also its constitutive expression, as well as TNF-α levels (27). Taken together, these results demonstrate a crucial role for glutamate in the initiation of a response that shares certain features with the inflammatory processes. These results highlight a direct central regulatory effect of stress-induced neuroinflammation to be added to the entry of cytokines from outside the brain.

NFκB is a transcription factor widely expressed in the CNS. It consists of homodimers or heterodimers of a family of structurally related proteins. The most commonly found type is the heterodimer composed of a p65 (RelA) and a p50 subunit. This dimer can also bind to a third protein called IκB, which inactivates NFκB. The activation of this transcription factor comprises the sequential activation of different enzyme complexes such as NFκB-induced kinase (NIK), which, in turn, activates IκB kinase (IKK) that catalyzes the phosphorylation of two serines in NFκB. This constitutes the signal for the degradation of IκB. Once free of the inhibitory subunit, NFκB can enter the nucleus where it binds to specific κB DNA consensus sequences in the enhancer region of a variety of κB-responsive genes, some of which are involved in oxidative-nitrosative damage (29).

Stress activates NFκB in brain cells as soon as 4 h after the onset of stress in rats (reviewed in Ref. 19) and potentiates the activity of this transcription factor in the frontal cortex and hippocampus of rats under endotoxic shock (induced by LPS) (9). This activation of NFκB after stress was confirmed in experiments with humans and transgenic mice subjected to psychological or immobilization stress (30).

Many stimuli such as viral and bacterial infection, glutamate, UV light, ionizing radiation, free radicals, and cytokines activate NFκB (29). One of these activators is TNF-α (31). The implication of TACE and TNF-α in stress-induced activation of NFkB was confirmed after finding that the pharmacological inhibition of TACE also blocked the stress-induced activation of NFκB (27).

Additionally, the essential role of NMDA activation as a trigger factor in this process is of particular interest, since blockade of this receptor decreases NFκB translocation induced by LPS (9), and also decreases stress-induced TACE activation and TNF-α release (19).

We will now examine the consequences of the activation of such a transcription factor, leading to the expression of several responsive genes such as those involved in oxidative/nitrosative products.

NFκB-related oxidative/nitrosative products in stress

Some of the genes responsive to NFκB are oxidative/nitrosative sources. These include inducible nitric oxide synthase (iNOS, NOS-2) and cyclooxygenase-2 (COX-2).

iNOS. Nitric oxide (NO) is synthesized from L-arginine by the enzymes NO synthases: endothelial, neuronal and an isoform expressed during inflammatory reactions (iNOS). iNOS is an enzyme expressed after exposure of cells to several noxious agents such as cytokines or LPS (32). This NOS isoenzyme mediates cytotoxicity in many cell systems, mainly because of the oxidative/nitrosative effects produced by extensive and prolonged release of NO, which finally lead to a production of other oxidant species such as peroxynitrite (33).

Evidence has been presented for the role of NO in some pathological processes in the CNS. Indeed, the excessive generation of NO has been demonstrated in epilepsy, hypoxic-ischemic damage and neurodegenerative disorders including Alzheimer's and Parkinson's diseases and Huntington's corea (32).

It has been reported that exposure to stress results in increased NO production in the brain and periphery. A similar transient stimulation of NO release also occurs in plasma of humans subjected to stress (reviewed in Ref. 19). This systemic release of NO may offset the vasoconstrictor and pro-aggregatory effects of stress hormones and mediators during the first stages of the stress response.

Immobilization stress increases brain iNOS activity and expression as soon as 6 h after the onset of stress (34), and longer periods of stress produce higher levels of iNOS expression and activity (reviewed in Ref. 19). The detrimental effects of the long-term stress induction of iNOS include accumulation of membrane aldehyde products (peroxidation products), disruption of blood brain barrier and mitochondrial impairment (19). Pharmacological data obtained using specific inhibitors of iNOS support the conclusion of the participation of iNOS in stress-induced damage. It is unclear whether NO per se is the effector molecule of neuronal damage. A persistent elevation of NO levels can result in generation of a potent oxidant, peroxynitrite (ONOO-) from superoxide and NO. Peroxynitrite is a tissue-damaging agent that acts by the initiation of lipid peroxidation, oxidation of sulfhydryl groups and nitrosation of tyrosine-containing molecules. The huge accumulation of NO and over-expression of iNOS observed in the brain during chronic stress probably leads to the production of reactive oxygen or nitrogen species such as peroxynitrite (19).

iNOS induction in stress depends on NFκB activation. This was supported by the use of an inhibitor of NFκB activation such as pyrrolidine dithiocarbamate, which decreased the activity and expression of iNOS in stressed animals (34).

Pharmacological experiments were carried out to study the possibility that cytokines and excitatory amino acids account for the stress-induced activation of iNOS. Indeed, specific blockers of the NMDA receptor of glutamate (MK-801) or TACE inhibitors (BB1101) partially inhibit the stress-induced iNOS expression and activation (25).

On the other hand, the COX pathway has also been implicated in stress-induced brain damage. COX-2 is induced in stress and has been involved in the damage associated with this condition. According to its condition of inducible enzyme, and similarly to iNOS, the promoter of the immediate-early gene COX-2 depends on the activation of NFκB in stress. Both enzymatic sources of oxidative mediators in the brain depend on the activation of the NMDA type of glutamate receptor, and, in the case of iNOS, its activation also depends on the release of TNF-α.


I think the difference in how this affects people with RRMS and SPMS/PPMS is here...could be wrong though. This is pretty new to me.
Energy deficiency and dysfunction of Na,K-ATPase are common consequences of many pathological insults and stress. Glutamate through cyclic guanosine monophosphate (GMP) and cyclic GMP-dependent protein kinase (PKG) has been shown to stimulate α2/3-Na,K-ATPase activity in the CNS (58). Thus, a slight impairment of this pathway may amplify the disruption of ion homeostasis in the presence of a non-lethal insult. Studies in rats suggest that basal age-related decline in sodium pump activity is a consequence of changes in different steps of the cyclic GMP-PKG pathway. On the other hand, age-related reduction in glutamate-positive modulation of cerebellar α2/3-Na,K-ATPase is linked to a defective PKG signaling pathway (59). The loss of the ability of α2/3-Na,K-ATPase to respond to glutamate through a cyclic GMP-PKG cascade could be a failure in an important mechanism for rectifying ionic disturbances that may be present in aging processes and may predispose to or potentiate an effect of stress in the manifestation of age-related degenerative disorders. In fact, chronic predictable and unpredictable stress decrease the neuronal Na,K-ATPase activity and high levels of glucocorticoid have been detected in 24-month-old rats (Munhoz CD, Scavone C, unpublished results), which could induce a further reduction of ATP levels during a neurological insult. It is interesting to note that the aging process (30-month-old animals) induces up-regulation in constitutive NFκB binding activity in the frontal cortex, which in the presence of glucocorticoid levels could potentiate LPS-induced NFκB activation and an increase in mRNA of proinflammatory genes (9). In addition, rats with increased HPA reactivity induced by prenatal stress or by the absence of neonatal handling show an early decline of cognitive functions associated with the hippocampus, as well as increased propensity to self-administer drugs such as amphetamine and cocaine (55). In addition, exposure to both chronic restraint and unpredictable stress increased cocaine-induced locomotion and basal corticosterone plasma levels and chronic unpredictable stress also displayed the largest locomotor response following a challenge dose with cocaine compared with control and chronic restraint stress groups (60). Drug abuse is associated with changes in brain function and neurodegenerative processes, which, for some drugs, have been shown to be associated with the induction of apoptotic/necrotic cell death (Lepsch LB, Munhoz CD, Kawamoto EM, Lima LS, Scavone C, unpublished results). Thus, life-long patterns of HPA function are probably important to determine the susceptibility of the body to stress or insults during the aging process.
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Re: Potential treatment for SPMS and/or PPMS

Postby Anonymoose » Fri Mar 15, 2013 2:10 pm

More support for involvement of glutamate and NMDA receptors (at least as one of several receptors)

Multiple sclerosis and glutamate excitotoxicity
Published Online:
2012-11-12
Abstract

The previous understanding of multiple sclerosis was solely related to neuroinflammation and its harmful effects; however, countless data indicate the importance of some inflammation-independent, neurodegenerative mechanisms associated with mitochondria malfunction, iron deposition and oxidative stress. Recently, it has been postulated that glutamate excitotoxicity, a phenomenon that takes place when an excessive amount of glutamate overactivates its cellular receptors and induces cell death, could be a missing link between inflammatory and neurodegenerative processes evident in multiple sclerosis. Glutamate is the major excitatory neurotransmitter of the central nervous system, which has been proven to have a central role in a complex communication network established between all residential brain cells, including neurons, astrocytes, oligodendrocytes and microglia. Thus, the disturbance of glutamate homeostasis could affect practically all physiological functions and interactions of brain cells, leading to heterogeneity of pathological events. The understanding of glutamate excitotoxicity as a valid mechanism of central nervous system damage in multiple sclerosis, requires the revision of the current knowledge about a source of elevated extracellular glutamate, glutamate receptor alterations, alterations of glutamate transporters and metabolizing enzymes, as well as molecular mechanism of excitotoxic damage.
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Re: Potential treatment for SPMS and/or PPMS

Postby Anonymoose » Sat Mar 16, 2013 5:49 am

A less toxic way of blocking NMDA receptors and calcium channels...zinc and magnesium. Jimmylegs is a genius!
http://www.ncbi.nlm.nih.gov/pubmed/21504727
Zinc effects on NMDA receptor gating kinetics.
Amico-Ruvio SA, Murthy SE, Smith TP, Popescu GK.
Source
Department of Biochemistry, University at Buffalo, Buffalo, New York, USA.
Abstract
Zinc accumulates in the synaptic vesicles of certain glutamatergic forebrain neurons and modulates neuronal excitability and synaptic plasticity by multiple poorly understood mechanisms. Zinc directly inhibits NMDA-sensitive glutamate-gated channels by two separate mechanisms: high-affinity binding to N-terminal domains of GluN2A subunits reduces channel open probability, and low-affinity voltage-dependent binding to pore-lining residues blocks the channel. Insight into the high-affinity allosteric effect has been hampered by the receptor's complex gating; multiple, sometimes coupled, modulatory mechanisms; and practical difficulties in avoiding transient block by residual Mg(2+). To sidestep these challenges, we examined how nanomolar zinc concentrations changed the gating kinetics of individual block-resistant receptors. We found that block-insensitive channels had lower intrinsic open probabilities but retained high sensitivity to zinc inhibition. Binding of zinc to these receptors resulted in longer closures and shorter openings within bursts of activity but had no effect on interburst intervals. Based on kinetic modeling of these data, we conclude that zinc-bound receptors have higher energy barriers to opening and less stable open states. We tested this model for its ability to predict zinc-dependent changes in macroscopic responses and to infer the impact of nanomolar zinc concentrations on synaptic currents mediated by 2A-type NMDA receptors.

http://www.ncbi.nlm.nih.gov/pubmed/18029156
Magnesium acts as a calcium channel antagonist

Too much zinc can be toxic so refer to Jimmylegs for advice on how to bring levels up.

I'm RRMS but I'm definitely going to be taking my zinc/mag.
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Re: Potential treatment for SPMS and/or PPMS

Postby jimmylegs » Sat Mar 16, 2013 3:58 pm

atta girl :D
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