Lithium upregulates growth-associated protein-43 (GAP-43) and postsynaptic density-95 (PSD-95) in cultured neurons exposed to oxygen-glucose deprivation and improves electrophysiological outcomes in rats subjected to transient focal cerebral ischemia following a long-term recovery period

ABSTRACT

Objectives

Lithium has numerous neuroplastic and neuroprotective effects in patients with stroke. Here, we evaluated whether delayed and short-term lithium treatment reduces brain infarction volume and improves electrophysiological and neurobehavioral outcomes following long-term recovery after cerebral ischemia and the possible contributions of lithium-mediated mechanisms of neuroplasticity.

Methods

Male Sprague Dawley rats were subjected to right middle cerebral artery occlusion for 90 min, followed by 28 days of recovery. Lithium chloride (1 mEq/kg) or vehicle was administered via intraperitoneal infusion once per day at 24 h after reperfusion onset. Neurobehavioral outcomes and somatosensory evoked potentials (SSEPs) were examined before and 28 days after ischemia-reperfusion. Brain infarction was assessed using Nissl staining. Primary cortical neuron cultures were exposed to oxygen-glucose deprivation (OGD) and treated with 2 or 20 μM lithium for 24 or 48 h; subsequent brain-derived neurotrophic factor (BDNF), growth-associated protein-43 (GAP-43), postsynaptic density-95 (PSD-95), and synaptosomal-associated protein-25 (SNAP-25) levels were analyzed using western blotting.

Results

Compared to controls, lithium significantly reduced infarction volume in the ischemic brain and improved electrophysiological and neurobehavioral outcomes at 28 days post-insult. In cultured cortical neurons, BDNF, GAP-43, and PSD-95 expression were enhanced by 24- and 48-h treatment with lithium after OGD.

Conclusion

Lithium upregulates BDNF, GAP-43, and PSD-95, which partly accounts for its improvement of neuroplasticity and provision of long-term neuroprotection in the ischemic brain.

Abbreviations: BDNF: brain-derived neurotrophic factor; ECM: extracellular matrix; EDTA: ethylenediaminetetraacetic acid; GAP-43: growth-associated protein-43; GSK-3β: glycogen synthase kinase-3β; HBSS: Hank’s balanced salt solution; LCBF: local cortical blood perfusion; LDF: laser-Doppler flowmetry; MCAO: middle cerebral artery occlusion; MMP: matrix metalloproteinase; NMDA: N-methyl-D-aspartate; NMDAR: N-methyl-D-aspartate receptor; OCT: optimal cutting temperature compound; OGD: oxygen-glucose deprivation; PSD-95: postsynaptic density-95; SDS: sodium dodecyl sulfate; SNAP-25: synaptosomal-associated protein-25; SSEP: somatosensory evoked potential

KEYWORDS:

• Ischemic stroke
• lithium
• neuroplasticity
• BDNF
• GAP-43
• PSD-95

Acknowledgments

We thank the Ministry of Science and Technology and the Office of Research-Animal Care of National Cheng Kung University for their research permission. Funding: Financial support was provided by the Ministry of Science and Technology in Taiwan (105-2314-B-006-075) and National Cheng Kung University Hospital (NCKUH-11004038).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by the Ministry of Science and Technology, Taiwan [105-2314-B-006-075]; National Cheng Kung University Hospital [NCKUH-11004038].

Notes on contributors

Shih-Huang Tai

Shih-Huang Tai, Associate professor in neurosurgical service, department of surgery, National Cheng Kung University hospital, college of medicine, National Cheng Kung University.

Sheng-Yang Huang

Sheng-Yang Huang, Post-doctoral Fellow of neurophysiology laboratory and neurosurgical service, department of surgery, National Cheng Kung University hospital, college of medicine, National Cheng Kung University.

Liang-Chun Chao

Liang-Chun Chao, Medical doctors in neurosurgical service, department of surgery, National Cheng Kung University hospital, college of medicine, National Cheng Kung University.

Yu-Wen Lin

Yu-Wen Lin, Post-Doctoral Fellow of neurophysiology laboratory and neurosurgical service, department of surgery, National Cheng Kung University hospital, college of medicine, National Cheng Kung University.

Chien-Chih Huang

Chien-Chih Huang, Research assistant of neurophysiology laboratory and neurosurgical service, department of surgery, National Cheng Kung University hospital, college of medicine, National Cheng Kung University.

Tian-Shung Wu

Tian-Shung Wu, Professor emeritus of the school of pharmacy, college of medicine, National Cheng Kung University. His research interests include traditional Chinese medicine, pharmacognosy, natural product medicinal chemistry.

Yan-Shen Shan

Yan-Shen Shan, professor of the Institute of Clinical Medicine, College of Medicine, National Cheng Kung University.

Ai-Hua Lee

Ai-Hua Lee, Research assistant of neurophysiology laboratory and neurosurgical service, department of surgery, National Cheng Kung University hospital, college of medicine, National Cheng Kung University.

E-Jian Lee

Ai-Hua Lee, Research assistant of neurophysiology laboratory and neurosurgical service, department of surgery, National Cheng Kung University hospital, college of medicine, National Cheng Kung University.

E-Jian Lee, professor in neurosurgical service, department of surgery, National Cheng Kung University hospital, college of medicine, National Cheng Kung University. He has a Ph.D. in biomedical engineering from NCKU. His research interests include cerebrovascular disease, brain aneurysm and AVM, cervical spine disorders and related instability, neurosurgical critical care.