Epileptogenic Effects of Several Penicillins and Penicillin‐Related Compounds in Rat Neocortex

Abstract

Several penicillins and penicillin-related compounds were tested for their ability to produce epileptiform activity in rat neocortex. (1) Alterations in the side chain of penicillin G decreased epileptogenic capability in all the compounds tested in this study: Phenoxymethylpenicillin produced a primary focus but no mirror focus, suggesting a dissociation of the mechanisms underlying these two processes. Ampicillin, 6-aminopenicillanic acid, and potassium 6-aminopenicillanic acid, and potassium 6-aminopenicillanic acid produced little or no epileptiform activity. All these compounds have free amino grounds and are amphoteric. (2) Breaking the beta lactam ring of penicillin G (potassium penicillin G penicilloate) eliminated epileptogenic capability. (3) Potassium salts of penicillin or its derivatives (potassium penicillin G, propicillin, potassium 6-aminopenicillanic acid, potassium penicillin G penicilloate) consistently suppressed cortical activity, regardless of the ability of the compound to produce spike discharges. Thus, mechanisms underlying these two properties can be dissociated. (4) Antibiotic activity of penicillins bears no relationship to epileptogenic capability.

Relationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats

“…The relative lipophilicities (R m s) and molecular weights of these ␤-lactam derivatives are summarized in Tables 1 and 2. DISCUSSION Previous studies have indicated that systemic administration of cephazolin to experimental animals produces epileptogenic effects (15,16,18,22), and the present results further confirm these findings.…”

“…The cephalosporins resemble penicillins in their actions as both antibiotics and convulsant compounds (27). Several investigators found that the ability of penicillin derivatives to produce a seizure focus was abolished after incubation with penicillinase (12,15,16). Since these studies support the idea that the ␤-lactam ring is an indispensable structural feature for epileptogenic activity of penicillins and cephalosporins, we decided to include in our study aztreonam, a monobactam, as well as two carbapenem compounds, imipenem and meropenem, and Ro 23-9424, made up of desacetyl-cefotaxime linked to fleroxacin (14).…”

Epileptogenic Activity of Cephalosporins in Rats and Their Structure‐Activity Relationship

“…Gerald et al (1973) found that the ability of penicillin derivatives to produce a seizure focus was abolished after incubation with penicillinase, an enzyme which splits the P-lactam ring of penicillins. Hartesveldt et al (1975) reported a similar observation: when potassium penicillin G penicilloate, a break-down product of penicillin G treated with penicillinase, was applied on rat neocortex, no spike discharge 432 C . KAMEI ET AL was provoked.…”

“…Therefore, it could be that the tetrazol group is responsible for the convulsive action of these cephalosporins. This assumption, however, is not valid, because the epilep- Hartesveldt et al (1975) reported that ampici11in and 6-aminopenici11anic acid 9 de Groat J, The rat forebrain in stereotaxic coordiwhich have both a carboxyl group and an amino group in their chemical structures, had little epileptogenic activity. As a possible reason for this finding, they proposed that amphoteric, polar properties of those compounds might interfere with the mechanisms leading to the seizure discharge.…”

Dual mechanisms of GABAa response inhibition by β‐lactam antibiotics in the pyramidal neurones of the rat cerebral cortex

“…So far, several authors have reported this relationship for M-lactam antibiotics. As for penicillins, it has been found that the ability to produce seizures was abolished after incubation with penicillinase, an enzyme which splits the IJ-lactam ring of penicillins (Gerald et al, 1973;Hartesvelt et al, 1975), which thus suggests that the P-lactam ring is an indispensible structure for epileptogenic activity of penicillin. In addition, the modification of the side chains at the 6 position of f-lactam ring of benzylpenicillin was associated with epileptic potency (Gutnic et al, 1976).…”