Table 2.
Antiepileptic and neuroprotective properties of ketamine in chemically induced seizures as reported in a selection of references. Two ways of administration were used: as a pretreatment (PTr) or as a treatment (Tr), usually after the SE has begun unless mentioned in the “note” column. In the column “ketamine effects”, the use of EEG recording has made possible the differentiation between an actual antiepileptic effect and an anticonvulsant action. The models that are the closest to the nerve agent‐induced SE are the lithium–pilocarpine and kainic acid models. The dose of ketamine is said variable when different doses were tested to establish the ED 50, without more details. SC, IP, IV subcutaneous, intraperitoneal, and intravenous routes, respectively. Experiments using pretreatment are less significant in the context of this review, and some cited in the text are not incorporated here
| Model | Animal species | Ketamine dose (mg/kg)/route/mode of administration | Ketamine effects; ED50 mg/kg (confidence interval 95%) | Note | References |
|---|---|---|---|---|---|
| Kainic acid | Rat | 1–20/SC/PTr | Neuroprotective despite persistence of epileptic discharges | Reinjections every 30 min. | 23 |
| Kainic acid | Rat | 50/IP/Tr | Antiepileptic | Not effective alone, effective with diazepam | 133 |
| Intrahippocampal pilocarpine | Rat | 50/IP/Tr | Moderate neuroprotection | SE stopped by thiopental. Repeated injection of ketamine afterwards | 134 |
| Lithium–pilocarpine | Rat | 100/IP/Tr | Antiepileptic (partial effect) and neuroprotective | 135 | |
| Lithium–pilocarpine | Rat | 100/IP/Tr | Neuroprotective/does not prevent epileptogenesis | 15 min after SE onset/or with clonazepam at 120 min | 136 |
| Lithium–pilocarpine | Rat | 100/SC/Tr | Neuroprotective (behavior and other long term consequences) | 5 min after convulsion onset | 128, 132, 137, 138, 139 |
| Lithium–pilocarpine | Rat | 100/SC/Tr | Robust cognitive/memory sparing despite neuronal damage | Idem | 129, 131, 140 |
| Lithium–pilocarpine | Rat | 50–100/IP/Tr | Antiepileptic (partial effect) | Doses below 100 mg/kg ineffective. Synergistic effects with diazepam | 141 |
| Lithium–pilocarpine | Rat | 22.5/IP/Tr | Anticonvulsant and neuroprotective (histology and behavior) | Young rats. Ketamine given either 15 or 60 min after injection of pilocarpine | 127 |
| Pilocarpine | Rat | 1.5–2/IP/PTr | Antiepileptic | Ketamine given 30 min prior to pilocarpine | 142 |
| Pilocarpine | Rat | 0.5–1/IP/PTr | Antiepileptic | Ketamine given 30 min prior to pilocarpine | 143 |
| Pilocarpine | Rat | 50/IP/Tr | Anticonvulsant and protection against memory deterioration | Ketamine given 2 min after onset of seizures | 144 |
| Soman | Guinea pig | 10–60/IM/Tr | Antiepileptic and neuroprotective | Repeated injections starting 30 min or 60 min post‐soman. Combined with atropine | 81 |
| Soman | Guinea pig | 15–20/IM/Tr | Anticonvulsant and neuroprotective | Repeated injections of S(+) ketamine starting 1 or 2 h post‐soman. Combined with atropine | 145 |
| Soman | Rat | 15/IP/Tr | No effect | 106 | |
| Soman | Mouse | 25–100/IP/Tr | Anticonvulsant and neuroprotective. Reduction of neuroinflammation | Repeated injections starting 30 min or 60 min post‐soman. Combined with atropine | 146 |
| Soman | Mouse | 100 then 50 twice/IP/Tr | Anticonvulsant and neuroprotective. Protection against some metabolic changes | Repeated injections starting 1 or 2 h post‐soman. Combined with atropine | 147 |
| NMDA | Rat pup | 50/IP/Tr | Anticonvulsant | 148 | |
| NMDA | Mouse | Variable/IP/PTr | Anticonvulsant ED50 45.9 (16.1–60.2) | 149 | |
| NMDA | Mouse | 10–55/IV/PTr | Anticonvulsant ED50 46.4 (33.0–67.5) | 37 | |
| NMDA | Rat/mouse | 10–50/IP/PTr or Tr | Antiepileptic | 150 | |
| NMDA | Mouse | Variable/IP/PTr | Anticonvulsant ED50 16 (11–22) | 151 | |
| NMDA | Mouse | Variable/IP/PTr | Anticonvulsant ED50 53.2 (23.3–121.5) | 152 | |
| NMDA (intrahippocampal) | Rat | 15, 60 or 180/IP/PTr or Tr | Partial neuroprotection as a delayed treatment | 153 | |
| Bicuculline | Rat | 10/SC/PTr followed by Tr | Neuroprotectant without any antiepileptic effect | Reinjections every 30 min. | 154 |
| Bicuculline | Rat | ≥30/IV/PTr | Anticonvulsant | 155 | |
| Bicuculline | Rat | 5–40/IP/Tr | Antiepileptic |
Rats of different ages Better efficacy against generalized tonic‐clonic seizures |
156 |
| Bicuculline | Mouse | Variable/IP/PTr | Anticonvulsant (tonic phase) ED50 15 (10–22) | 157 | |
| Focal seizures (penicillin injection) | Cat | 5–20/IV/Tr | Antiepileptic (transiently) | 3–4 injections at 1–1.5 h interval | 158 |
| Focal seizures (penicillin injection) | Rabbit | 20–40/IV/Tr | Antiepileptic (for 20–30 min.) | 159 | |
| Pentylenetetrazol (PTZ, metrazol) | Rat | 5–100/IP/PTr | Antiepileptic | 160 | |
| Pentylenetetrazol (PTZ, metrazol) | Mouse | 0.1–5/IP/PTr | Antiepileptic | Increase seizure threshold | 161 |
| Pentylenetetrazol (PTZ, metrazol) | Rat | 1–40/IP/Tr | Antiepileptic |
Rats of different ages Better efficacy against generalized tonic‐clonic seizures |
162 |
| Mercaptopropionate and PTZ | Mouse | 90/IP/PTr | Anticonvulsant | 163 | |
| Mercaptopropionate | Rat | 30 (followed by infusion 9.12 mg/kg.h for 2 h/IV/Tr | Antiepileptic | Experiments in paralyzed rats | 164 |
| Picrotoxin | Rat | 20–100/IP/Tr | Antiepileptic (partial effect) | Treatment before the onset of seizures | 160 |
| Picrotoxin | Rat | 5–40/IP/Tr | Antiepileptic |
Rats of different ages Better efficacy against generalized tonic‐clonic seizures |
156 |
| Lidocaine | Mouse | 165 | |||
| 4‐aminopyridine | Rat | 3/IP/PTr | Delay 4‐AP‐induced convulsions and % of animals with convulsions. Partial reduction of cFOS immunoreactivity | Ketamine injected 10 min before 4‐AP | 166 |
| Tetramethylenedisul‐fotetramine | Mouse |
35–70/IP/Tr 35/IP/PTr |
Anticonvulsant at 70 mg/kg Not anticonvulsant – increases survival |
Early administration at first clonic convulsions | 167 |
| Guanidinosuccinic acid | Rat | 60/IP/PTr – Tr | Antiepileptic and neuroprotective | 1 dose prior and 1 dose at 60 min | 168 |