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Foun another interesting drug: Acamprosate


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This one looks interesting. I wrote about it before in a different post, but decided to make a new one.

It looks safe and it's description hits few interesting keywords, glutamate caused excitability and been anecdotally reported to work on tinnitus, which is an HPPD symptom, and might therefore be implicated in its pathophysiology.

 

Drug's name: Acamprosate

 

Drug class:
NDMA modulator, depending on concentration/dose applied (possibly weak antagonism action at NMDA receptor)
Effect on Calcium Channels
Neuroprotective Effects
 
Used as treatment for:
  • Alcohol dependence/withdrawal
  • Tinnitus
Effect on HPPD (Anecdotal experiences):
 
No references on HPPD communities, one reference on Those With Visual Snow forum
  • Not any known anecdotal experiences, open to experimentation
 
Side effects:
 
Diarrhea, nausea, anxiety, depression
 
Study: Role of acamprosate in sensorineural tinnitus
 
Acamprosate has low bioavailability, but also has an excellent tolerability and safety profile. 
 
Mechanism of action of acamprosate. Part I. Characterization of spermidine-sensitive acamprosate binding site in rat brain.
 
... The results show that acamprosate binds to a specific spermidine-sensitive site that modulates the NMDA receptor in a complex way. Together, with data from al Quatari et al. (see next paper), this work suggests that acamprosate acts as "partial co-agonist" at the NMDA receptor, so that low concentrations enhance activation when receptor activity is low, whereas higher concentrations are inhibitory to high levels of receptor activation. This may be relevant to the clinical effects of acamprosate in alcohol-dependent patients during abstinence.
 
 
page 10:
Initial studies postulated that acamprosate might affect central neurones through an activation of the GABA neurotransmission (19,20). However, this hypothesis has been practically ruled out. Acamprosate does not seem to affect GABAreceptor mediated trans mission.
 
Since approximately 1997, investigators re-directed their efforts and explored three
possible mechanisms of action of acamprosate (31,60):
— interaction of acamprosate with N-methyl-D-aspartate (NMDA) receptors;
— blockade of voltage-dependent Ca2+ channels;
— changes in NMDA receptor subunit composition.
 
In this section we review data that support these three hypotheses.
 
....However, it is not clear whether acamprosate enhances or inhibits NMDA re-
ceptor function....
 
Zeise et al. (66),using in vivo electrophysiological recordings and in vitro techniques, reported in 1993 that acamprosate reduces the activation of synapses controlled by L-glutamate (L-Glu) in the
rat neocortex. These authors showed, for the first time, that acamprosate potently and reversibly reduces depolarizing responses induced by several excitatory amino acids, including L-Glu and NMDA.
 
The interaction of acamprosate with NMDA receptors has also been studied using other in vitro techniques. So, Allgaier et al. (1) studied the effect of the drug on the Ca2+ influx evoked by NMDA in cultured neurons. The results obtained by these authors clearly show that acamprosate significantly reduces NMDA-induced elevation in free intracellular Ca2+ concentration. Similarly, Al-Qatari et al. (3) showed that acamprosate inhibits glutamate-induced calcium entry in cultures of neocortical neurons without affecting glutamate...
.... Taken together, it seems clear that acamprosate reduces glutamatergic neurotransmission....
 
 
Blockade of Voltage-Dependent Ca2+Channels
In addition to the above described interaction with the NMDA receptors, acamprosate has been found to block the voltage-gated Ca2+ channels. This effect could also be responsible for the reduction of neuronal hyperexcitability by acamprosate during alcohol withdrawal.
Initially, it has been reported that acamprosate displaces Ca2+ channel antagonists from a low-affinity site on brain membranes and inhibits the upregulation of Ca2+channels in alcohol-withdrawn rats (4). More recently, Allgaier et al. (1) reported that in rat cultured mesencephalic neurons acamprosate antagonizes K-induced increase in intracellular Ca2+ concentration in a concentration-dependent manner
 
Taken together, it seems clear that acamprosate reduces glutamatergic neurotransmission. At this moment it is not clear whether these effects are a result of a direct interaction with the NMDA receptor channel or with the polyamines-sensitive binding site at the NMDA receptor. Acamprosate seems to act as a functional antagonist at the NMDA receptor system counterbalancing chronic ethanol-induced changes. This would lead to a reduction of neuronal hyperexcitability during the true and the conditioned ethanol withdrawal.
 
Blockade of Voltage-Dependent Ca2+ Channels
In addition to the above described interaction with the NMDA receptors, acamprosate has been found to block the voltage-gated Ca2+ channels. This effect could also be responsible for the reduction of neuronal hyperexcitability by acamprosate during alcohol withdrawal.
Initially, it has been reported that acamprosate displaces Ca2+ channel antagonists from
a low-affinity site on brain membranes and inhibits the upregulation of Ca2+ channels in
alcohol-withdrawn rats (4). More recently, Allgaier et al. (1) reported that in rat cultured
mesencephalic neurons acamprosate antagonizes K-induced increase in intracellular Ca2+
concentration in a concentration-dependent manner.
 
Changes in NMDA Receptor Subunit Composition
In 2001, Rammes et al. (51) reported that acute acamprosate (and other well estab-
lished NMDA antagonists such as memantine and MK-801) increased the expression of
specific NMDA-receptor subunits in selected brain areas. This phenomenon could con-
stitute a novel pharmacological explanation of the mechanism of action of this drug.
Importantly, upregulation has been selectively observed in the cortex and hippocampus
and no changes were detected in the brainstem. In the cortex, the changes in protein expression were detected after a single i.p. dose of 200 mg/kg of acamprosate; they affected mainly the NMDAR1–3/1–4 and NMDAR2B subunits. In the hippocampus two injections of acamprosate, 200 mg/kg i.p., separated by a 12-h interval, increased protein expression of all subunits investigated (NMDAR1–1/1–2; NMDAR1–3/1–4; NMDAR2B).
These data strongly suggest that NMDA-receptor subunit expression can be rapidly
and region-dependently increased after acute exposure to acamprosate. Provided that
changes in NMDA-receptor subunits composition could induce changes in functional
characteristics of these receptors in the brain regions affected, the modulation induced by
acamprosate may constitute a novel explanation of the mode of action of this drug.
However, more experiments are necessary to properly characterize the neurochemical
consequences of these changes in the transcription of NMDA receptor subunits.
A new hypothesis to explain the mechanism of action of acamprosate has been recently
proposed (26). According to this hypothesis acamprosate exerts its effects through interactions with the group I metabotropic receptors for glutamate (I mGluR). Harris et al. (26)
found that acamprosate inhibits the binding of trans-ACPD (a well recognized agonist of
the group I and II metabotropic glutamate receptors) to AP2 membrane preparations of
several rat brain areas. Moreover, acamprosate was neuroprotective against trans-ACPD
induced neurotoxicity in organotypic hippocampal slice cultures. Hence, in the opinion of the authors, acamprosate’s binding and functional characteristics are consistent with it
being a group I mGluR antagonist.

 

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