Korean J Physiol Pharmacol.  2017 Jan;21(1):125-131. 10.4196/kjpp.2017.21.1.125.

Neuroprotective effect of lithium after pilocarpine-induced status epilepticus in mice

• Hong N
• Choi YS
• Kim SY
• Kim HJ

• KMID: 2371076
• DOI: http://doi.org/10.4196/kjpp.2017.21.1.125

Abstract

Status epilepticus is the most common serious neurological condition triggered by abnormal electrical activity, leading to severe and widespread cell loss in the brain. Lithium has been one of the main drugs used for the treatment of bipolar disorder for decades, and its anticonvulsant and neuroprotective properties have been described in several neurological disease models. However, the therapeutic mechanisms underlying lithium's actions remain poorly understood. The muscarinic receptor agonist pilocarpine is used to induce status epilepticus, which is followed by hippocampal damage. The present study was designed to investigate the effects of lithium post-treatment on seizure susceptibility and hippocampal neuropathological changes following pilocarpine-induced status epilepticus. Status epilepticus was induced by administration of pilocarpine hydrochloride (320 mg/kg, i.p.) in C57BL/6 mice at 8 weeks of age. Lithium (80 mg/kg, i.p.) was administered 15 minutes after the pilocarpine injection. After the lithium injection, status epilepticus onset time and mortality were recorded. Lithium significantly delayed the onset time of status epilepticus and reduced mortality compared to the vehicle-treated group. Moreover, lithium effectively blocked pilocarpine-induced neuronal death in the hippocampus as estimated by cresyl violet and Fluoro-Jade B staining. However, lithium did not reduce glial activation following pilocarpine-induced status epilepticus. These results suggest that lithium has a neuroprotective effect and would be useful in the treatment of neurological disorders, in particular status epilepticus.

Keyword

Lithium; Neuroprotection; Pilocarpine; Seizure susceptibility; Status epilepticus

MeSH Terms

Animals
Bipolar Disorder
Brain
Hippocampus
Lithium*
Mice*
Mortality
Nervous System Diseases
Neurons
Neuroprotection
Neuroprotective Agents*
Pilocarpine
Receptors, Muscarinic
Seizures
Status Epilepticus*
Viola
Lithium
Neuroprotective Agents
Pilocarpine
Receptors, Muscarinic

Figure

• 

  Fig. 1 Neuroprotective effect of lithium in the mouse hippocampus after pilocarpine-induced SE as evaluated by cresyl violet staining.(A) Representative images of cresyl violet-stained brain coronal sections 3 days after pilocarpine-induced SE. Treatment with lithium chloride (80 mg/kg) protected the CA1, CA3 and hilus cells of the hippocampus 15 min after pilocarpine injections. The scale bars in i and l indicate 1 mm and 100 µm, respectively. (B), (C) Quantitative analysis of neuronal damage in the sham-, vehicle-, and LiCl-treated groups, respectively. *p<0.05 relative to sham. **p<0.05 relative to vehicle.

• 

  Fig. 2 Lithium reduces neuronal cell death in the mouse hippocampus after pilocarpine-induced SE.(A) Representative images of Fluoro Jade B-stained brain coronal sections 3 days after pilocarpine-induced SE. Treatment with lithium chloride (80 mg/kg) protected the CA1, CA3 and hilus cells of the hippocampus 15 min after pilocarpine injection. The scale bars indicate 100 µm. (B), (C) Quantitative analysis of neuronal damage in the vehicle- and LiCl-treated groups. *p<0.05 relative to vehicle.

• 

  Fig. 3 Astrocyte activation in the hilus.Representative images of GFAP immunoreactivity from sham-treated animals (A and A1), vehicle-treated animals (B and B1) and LiCl-treated animals (C and C1). Animals were perfused at 3 days after the pilocarpine-induced SE. The scale bars in C and C1 indicate 200 µm and 100 µm, respectively.

• 

  Fig. 4 Microglia activation in CA3.Representative images of immunoreactivity to CD11b, a marker of activated microglia, from sham-treated animals (A and A1), vehicle-treated animals (B and B1) and LiCl-treated animals (C and C1). Animals were perfused at 3 days after the pilocarpine-induced SE. The scale bars in C and C1 indicate 200 µm and 100 µm, respectively.

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