Basic NeuroscienceInvited reviewChemically-induced TLE models: Topical application
Section snippets
Topical application of convulsant drugs
Epilepsy is a condition of the brain characterized by recurrent seizures that affect 1–2% (Hesdorffer et al., 2011) of the population worldwide. Mesial temporal lobe epilepsy (MTLE) is the most frequent form of focal epilepsy in adults and at least 70% of patients presenting with MTLE are resistant to currently available medication (Schmidt and Löscher, 2005, Engel, 2001). Most patients with refractory TLE display severe unilateral hippocampal atrophy, so-called hippocampal sclerosis (HS),
Unilateral intraamygdala injection of KA
Microinjection of KA into the amygdala of rats was established in the late 1970s by Ben-Ari et al. (1978). In this and subsequent studies it was shown that focal administration of KA triggers convulsive seizures, which start at the site of injection and then spread via the cortex and ipsilateral hippocampus to the contralateral amygdala and contralateral hippocampus (Ben-Ari et al., 1978, Ben-Ari, 1985). Intriguingly, several studies demonstrated that early after KA injection, the most
Unilateral intrahippocampal injection of KA
The first study showing that unilateral injection of 5–20 nmol KA into the hippocampus of rats induces seizures and unilateral hippocampal atrophy, gliosis and neurodegeneration was performed by Schwarcz et al. (1978). In later studies, KA injection into the hippocampal CA1 or CA3 region of anesthetized rats (0.4–2.0 μg) evoked convulsive SE and the development of SRS after a latent period of 5–21 d (Cavalheiro et al., 1982, Bragin et al., 1999). However, Bragin et al. (1999) reported that only
Unilateral intracortical injection of KA
Recently, Bedner et al. (2015) injected KA (70 nl, 1.4 nM) into the neocortex just above the right dorsal hippocampus of anesthetized mice. This treatment reliably caused SE and, in contrast to the intrahippocampal KA administration in mice, consistently provoked convulsive behavior. Continuous surface EEG recording revealed series of high-frequency and high-amplitude seizures starting directly after injection and persisting for up to 12 h (mean duration 4.4 ± 2.4 h) (Fig. 2A). Behavioral assessment
Intracerebral injection of pilocarpine
Pilocarpine has been shown to trigger acute and chronic seizures after intracerebroventricular and intrahippocampal administration (Croiset and De, 1992, Millan et al., 1993, Smolders et al., 1997, Lindekens et al., 2000, Furtado et al., 2002, Furtado et al., 2011, Castro et al., 2011, Medina-Ceja et al., 2014). Detailed behavioral, electrophysiological and morphological analyses have been performed in mice by Furtado et al., 2002, Furtado et al., 2011. They showed that unilateral hippocampal
Intrahippocampal and intracortical application of tetanus toxin
The first reports of seizures caused by intracerebral application of tetanus toxin go back to the late 19th century (Roux and Borrel, 1889). In the modern era Mellanby and colleagues developed intrahippocampal injection of minute doses (10–20 mouse lethal doses in <1 μl) of tetanus toxin as a means of inducing SRS (Mellanby et al., 1977). The toxicity of different batches of tetanus toxin varies considerably, so it can be more reliable to express dose in lethal doses rather than weight of
Drug resistance
One of the major aims of epilepsy research is to overcome the problem of resistance to antiepileptic drugs (Stables et al., 2003). The models outlined above do show evidence of drug resistance, and therefore can contribute to this research. In the case of the rat intrahippocampal tetanus toxin model, carbamazepine and lamotrigine reduce seizure frequency significantly (Doheny et al., 2002), but not to below half the baseline rate, which is widely considered as the minimum requirement for an
Other topically administered substances inducing epileptogenesis
Several other convulsants have been used to induce seizures and hippocampal pathology, including bicuculline methiodide, picrotoxin, 4-aminopyridine and quinolinic acid (Schwarcz et al., 1984, Turski et al., 1985, Fisher, 1989, Sierra-Paredes and Sierra-Marcuno, 1996, Pena and Tapia, 1999, Sarkisian, 2001). Intrahippocampal injection of low doses of bicuculline methiodide (<1 nmol), a GABAA receptor antagonist, has been shown to reliably provoke recurrent motor seizures in the absence of
Concluding remarks
Topical application or injection of a variety of agents can induce the process of epileptogenesis and cause chronic epileptic foci. The choice of which disease model to use depends on the question asked. The models towards the end of this paper address potential etiological factors in clinical epilepsy (e.g. hemorrhage, ischemia or disruption of the blood brain barrier). The more commonly used models mentioned at the start of our review (KA, pilocarpine and tetanus toxin) recapitulate to a
Acknowledgements
The original work by the authors was supported by the following grants: Deutsche Forschungsgemeinschaft (STE 552/3-1) and European Science Foundation (EuroEPINOMICS) to CS; Medical Research Council (G0802162) and Epilepsy Research UK (P1102) to JJ. We thank Dr. Ines Heuer for technical support.
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2021, Neurobiology of DiseaseCitation Excerpt :Initially designed for rats (Turski et al., 1983), the pilocarpine protocol was then developed for mice (Cavalheiro et al., 1996; Gröticke et al., 2007), enabling the use of transgenic lines that are powerful tools for research. On the other hand, the low survival and the low SE induction rates are traditionally considered major obstacles in the systemic pilocarpine treatment in mice (Ahmed Juvale and Che Has, 2020; Buckmaster and Haney, 2012; Cavalheiro et al., 1996; Jefferys et al., 2016; Schauwecker, 2012; Shibley and Smith, 2002; Winawer et al., 2007). It was postulated that high mortality in pilocarpine-injected mice might be caused by cardiovascular complications and respiratory failure consecutive to SE (Blair et al., 2009; Buckmaster and Haney, 2012).
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