Monoamine oxidase inhibitors were among the first antidepressants to be discovered and have long been used as such. It now seems that many of these agents might have therapeutic value in several common neurodegenerative conditions, independently of their inhibition of monoamine oxidase activity. However, many claims and some counter-claims have been made about the physiological importance of these enzymes and the potential of their inhibitors. We evaluate these arguments in the light of what we know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitors.

The therapeutic potential of monoamine oxidase inhibitors.

Chesler, Mitchell. Regulation and Modulation of pH in the Brain. Physiol Rev 83: 1183-1221, 2003; 10.1152/physrev.00010.2003.—The regulation of pH is a vital homeostatic function shared by all tiss...

https://www.physiology.org/doi/pdf/10.1152/physrev.00010.2003

Regulation and Modulation of pH in the Brain

Migraine is one of the most frequent disabling neurological conditions with a major impact on the patients' quality of life. To give evidence-based or expert recommendations for the different drug treatment procedures of the different migraine syndromes based on a literature search and an consensus in an expert panel. All available medical reference systems were screened for all kinds of clinical studies on migraine with and without aura and on migraine-like syndromes. The findings in these studies were evaluated according to the recommendations of the EFNS resulting in level A,B, or C recommendations and good practice points. For the acute treatment of migraine attacks, oral non-steroidal anti-inflammatory drugs (NSAIDs) and triptans are recommended. The administration should follow the concept of stratified treatment. Before intake of NSAIDs and triptans, oral metoclopramide or domperidon is recommended. In very severe attacks, intravenous acetylsalicylic acid or subcutaneous sumatriptan are drugs of first choice. A status migrainosus can probably be treated by steroids. For the prophylaxis of migraine, betablockers (propranolol and metoprolol), flunarizine, valproic acid, and topiramate are drugs of first choice. Drugs of second choice for migraine prophylaxis are amitriptyline, naproxen, petasites, and bisoprolol.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1468-1331.2009.02748.x

EFNS guideline on the drug treatment of migraine--revised report of an EFNS task force.

Recent advances in microbial genomics, synthetic organic chemistry and X-ray crystallography provided opportunities to identify novel antibacterial targets for the development of new classes of antibiotics and to design more potent antimicrobial compounds derived from existing antibiotics in clinical use for decades. The antimetabolites, sulfa drugs and trimethoprim (TMP)-like agents, are inhibitors of three families of enzymes. One family belongs to the carbonic anhydrases, which catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. The other two enzyme families are involved in the synthesis of tetrahydrofolate (THF), i.e. dihydropteroate synthase (DHPS) and dihydrofolate reductase. The antibacterial agents belonging to the THF and DHPS inhibitors were developed decades ago and present significant bacterial resistance problems. However, the molecular mechanisms of drug resistance both to sulfa drugs and TMP-like inhibitors were understood in detail only recently, when several X-ray crystal structures of such enzymes in complex with their inhibitors were reported. Here, we revue the state of the art in the field of antibacterials based on inhibitors of these three enzyme families.

https://www.tandfonline.com/doi/pdf/10.3109/14756366.2013.787422

Sulfa and trimethoprim-like drugs – antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors

The mammalian Slc4 (Solute carrier 4) family of transporters is a functionally diverse group of 10 multi-spanning membrane proteins that includes three Cl-HCO3 exchangers (AE1–3), five Na+-coupled ...

https://www.physiology.org/doi/pdf/10.1152/physrev.00023.2012

The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters

Summary: Purpose: To identify and characterize the mutation(s) causing nocturnal frontal lobe epilepsy in a German extended family.



Methods: Neuronal nicotinic acetylcholine receptor (nAChR) subunit genes were screened by direct sequencing. Once a CHRNA4 mutation was identified, its biophysical and pharmacologic properties were characterized by expression experiments in Xenopus oocytes.



Results: We report a new CHRNA4 mutation, causing a α4-T265I amino acid exchange at the extracellular end of the second transmembrane domain (TM). Functional studies of α4-T265I revealed an increased ACh sensitivity of the mutated receptors. α4-T265I is associated with an unusual low penetrance of the epilepsy phenotype. Sequencing of the TM1-TM3 parts of the 1 known nAChR subunits did not support a two-locus model involving a second nAChR sequence variation.



Conclusions: nAChR mutations found in familial epilepsy are not always associated with an autosomal dominant mode of inheritance. α4-T265I is the first nAChR allele showing a markedly reduced penetrance consistent with a major gene effect. The low penetrance of the mutation is probably caused by unknown genetic or environmental factors or both.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1528-1157.2003.61102.x

A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy.

Summary:  Purpose: Headache is often ignored as a symptom of epileptic seizures. The purpose of this prospective study was to analyze frequency, classification, and characteristics of seizure-associated headache (SH) according to the criteria of the International Headache Society.



Methods: Over a period of 15 months, 341 patients with epilepsy, consecutively evaluated at our outpatient clinic for SH, completed a standardized questionnaire.



Results: Of the 341 epilepsy patients, 115 (34%) experienced SH with a pain intensity of 6.1 ± 1.6 (SD) on the visual analogue scale and a duration of 12.8 ± 15.7 (SD) h. Seizures were always accompanied by headache in 69 (60%) of these 115 patients. SH occurred in four (3%) of 115 patients only preictally, in 31 (27%) of 115 patients periictally, and in 80 (70%) of 115 patients only postictally. In the majority of the 115 patients (55.7%), SH could be classified as migraine headache, whereas in 36.5%, as tension-type headache. The type of SH was not correlated with sex, an epilepsy syndrome, or a seizure type. Migraine-like SH was significantly associated with a history of migraine (p < 0.001). In 20 (77%) of the 26 patients experiencing migraine-like SH with a history of migraine, the phenomenology of migraine-like SH and migraine attacks was identical.



Conclusions: SH is a frequent, long-lasting, and severe symptom of epileptic seizures, causing major impairment of daily living. A history of migraine significantly increases the risk for developing migraine-like SH.

Seizure‐Associated Headache in Epilepsy

Summary: Purpose: Sulthiame is a carbonic anhydrase (CA) inhibitor with an anticonvulsant effect in the treatment of benign and symptomatic focal epilepsy in children. The aim of the study was to elucidate the mode of action of sulthiame with respect to possible changes of intracellular pH (pHi) that might develop along with sulthiame’s anticonvulsant properties. Methods: The effects of sulthiame (a) on pHi of 2,7-bis(2carboxyethyl)-5(6)-carboxyfluorescein-acetoxymetyl ester (BCECF-AM) loaded CA3 neurones as well as (b) on epileptiform activity (induced by 50 M 4-aminopyridine) were compared with those of the CA inhibitors acetazolamide and benzolamide. Results: In the majority of neurons, sulthiame (1.0–1.5 mM; n 8) as well as the membrane permeant acetazolamide (0.5– 1.0 mM; n 6) reversibly decreased pHi by 0.18 ± 0.05 (SD) and 0.17 ± 0.10 (SD) pH units, respectively, within 10 min. The poor membrane permeant benzolamide (1.0–2.0 mM) had no influence on pHi (n 8). Sulthiame (1.0–2.5 mM) and acetazolamide (1.0–2.0 mM) reversibly reduced the frequency of action potentials and epileptiform bursts after 10–15 min (n 9, n 7), whereas benzolamide (1.0–2.0 mM) had no effect (n 6). Conclusions: The results suggest that sulthiame acts as a membrane-permeant CA inhibitor whose beneficial effect on epileptiform activity results at least in part from a modest intracellular acidosis of central neurons. Key Words: Sulthiame—Intracellular pH—Benzolamide—Acetazolamide— Carbonic anhydrase inhibitor.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1528-1157.2002.32601.x

Carbonic anhydrase inhibitor sulthiame reduces intracellular pH and epileptiform activity of hippocampal CA3 neurons.

Objective.—The study compared efficacy and tolerability of intravenous valproate (iVPA) with intravenous lysine-acetylsalicylic acid (iLAS) in acute migraine attacks.



Background.—iLAS has been proven to be a highly effective treatment in acute migraine attacks, but it is not available in many countries and contraindicated in patients with asthma or peptic ulcers. Current data suggest that iVPA may be effective in the treatment of acute migraine attacks.



Design/Methods.—In this randomized, double-blind, parallel-group phase-II study, 40 patients with acute migraine attacks (onset <5 hours, severe or moderate headache on a four-point IHS scale) alternately received iVPA 800 mg or iLAS 1000 mg. Primary outcome criteria were the percentage of patients reporting pain relief after 1 hour and patients who remained sustained pain free for 24 hours following drug administration. Secondary outcome criteria were relief of pain and associated migrainous symptoms (nausea, photophobia, and phonophobia) at 1, 2, 24, and 48 hours following drug administration.



Results.—There were no significant differences in demographic and clinical features between both treatment groups. Percentage of pain relief after 1 hour in the iVPA and iLAS groups were 25% and 30%, respectively, and of sustained pain free for 24 hours were 20% and 30%, respectively, without significant differences (P= 1 and P= .72, respectively). Both drugs improved associated migrainous symptoms without significant differences at the different time points, but again with a trend in favor of iLAS. No adverse events were observed.



Conclusion.—Both drugs were effective in acute migraine attacks with a trend in favor of iLAS. As both drugs were well tolerated, further studies with higher doses of iVPA for the treatment of acute migraine attacks are recommended.

Comparison of intravenous valproate with intravenous lysine-acetylsalicylic acid in acute migraine attacks.

Topiramate (TPM) is an anticonvulsant whose impact on firing activity and intracellular pH (pHi) regulation of CA3 neurons was investigated




Using the 4-aminopyridine-treated hippocampal slice model bathed in bicarbonate-buffered solution, TPM (25–50 μM) reduced the frequency of epileptiform bursts and action potentials without affecting membrane potential or input resistance Inhibitory effects of TPM were reversed by trimethylamine-induced alkalinization




TPM also lowered the steady-state pHi of BCECF-AM-loaded neuronal somata by 018±007 pH units in CO2/HCO3−-buffered solution Subsequent to an ammonium prepulse, TPM reduced the acidotic peak but clearly slowed pHi recovery These complex changes were mimicked by the protein phosphatase inhibitor okadaic acid




Alkalosis upon withdrawal of extracellular Cl− was augmented by TPM Furthermore, at decreased pHi due to the absence of extracellular Na+, TPM reversibly increased pHi These findings demonstrate that TPM modulates Na+-independent Cl−/HCO3− exchange




In the nominal absence of extracellular CO2/HCO3− buffer, both steady-state pHi and firing of epileptiform bursts remained unchanged upon adding TPM However, pHi recovery subsequent to an ammonium prepulse was slightly increased, as was the case in the presence of the carbonic anhydrase (CA) inhibitor acetazolamide Thus, a slight reduction of intracellular buffer capacity by TPM may be due to an inhibitory effect on intracellular CA




Together, these findings show that TPM lowers neuronal pHi most likely due to a combined effect on Na+-independent Cl−/HCO3− exchange and CA The apparent decrease of steady-state pHi may contribute to the anticonvulsive property of TPM






British Journal of Pharmacology (2004) 142, 831–842 doi:101038/sjbjp0705850

/pdf/topiramate-modulates-ph-of-hippocampal-ca3-neurons-by-3hvk2nj84n.pdf

Tobias Leniger

Papers

A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy.

Seizure‐Associated Headache in Epilepsy

Carbonic anhydrase inhibitor sulthiame reduces intracellular pH and epileptiform activity of hippocampal CA3 neurons.

Comparison of intravenous valproate with intravenous lysine-acetylsalicylic acid in acute migraine attacks.

Topiramate modulates pH of hippocampal CA3 neurons by combined effects on carbonic anhydrase and Cl-/HCO3- exchange.