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.

• Authors: Shih-Huang Tai, Sheng-Yang Huang, Liang-Chun Chao, Yu-Wen Lin, Chien-Chih Huang, Tian-Shung Wu, Yan-Shen Shan, Ai-Hua Lee, E-Jian Lee
• Journal: Neurological research (Neurol Res) Vol. 44 Issue 10 Pg. 870-878 (Oct 2022) ISSN: 1743-1328 [Electronic] England
• PMID: 35348035 (Publication Type: Journal Article)

Chemical References

• Brain-Derived Neurotrophic Factor
• Disks Large Homolog 4 Protein
• Dlg4 protein, rat
• GAP-43 Protein
• Neuroprotective Agents
• Receptors, N-Methyl-D-Aspartate
• Sodium Dodecyl Sulfate
• N-Methylaspartate
• Lithium
• Edetic Acid
• Glycogen Synthase Kinase 3 beta
• Lithium Chloride
• Glucose
• Oxygen

Topics

• Animals
• Brain Ischemia (drug therapy, metabolism)
• Brain-Derived Neurotrophic Factor (metabolism)
• Disks Large Homolog 4 Protein (metabolism)
• Edetic Acid
• GAP-43 Protein (metabolism)
• Glucose
• Glycogen Synthase Kinase 3 beta (metabolism)
• Infarction, Middle Cerebral Artery (metabolism)
• Lithium (pharmacology)
• Lithium Chloride (pharmacology)
• Male
• N-Methylaspartate
• Neurons (metabolism)
• Neuroprotective Agents (pharmacology)
• Oxygen
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Sodium Dodecyl Sulfate