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Disruption of Extracellular Signal-Regulated Kinase Partially Mediates Neonatal Isoflurane Anesthesia-Induced Changes
Swati Agarwal1, Jacqueline Bochkova2, Mazen K Mohamed2
1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Insights
Anesthesia can harm infant brain development, causing cognitive and behavioral issues. Pizotifen treatment protected against these effects by maintaining key molecular pathways involved in memory and synaptic plasticity.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Anesthesia exposure in early life is linked to cognitive deficits and attention disorders.
- Inhaled anesthetics disrupt synaptic plasticity by affecting postsynaptic density (PSD)-95 PDZ2 domain interactions.
- This disruption leads to impaired learning, memory, and reduced spine density in juvenile mice.
Purpose of the Study:
- To investigate the neuroprotective effects of pizotifen against anesthesia-induced cognitive impairments.
- To elucidate the molecular mechanisms underlying anesthesia's effects on synaptic plasticity and memory formation.
- To determine if pizotifen can prevent long-term cognitive deficits and structural changes in the brain.
Main Methods:
- Mice were exposed to isoflurane or PSD95-PDZ2-wildtype peptides to mimic anesthesia effects.
- Pizotifen treatment was administered post-exposure.
- Levels of phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated cAMP-response element binding protein (p-CREB) were measured.
- Learning, memory, and mushroom spine density were assessed at different ages.
Main Results:
- Isoflurane or peptide exposure decreased p-ERK and p-CREB levels, impairing synaptic plasticity and memory.
- Pizotifen treatment prevented the decline in p-ERK levels.
- Pizotifen preserved learning and memory functions and maintained mushroom spine density.
- Pizotifen's effects were linked to nitric oxide and ERK/CREB pathway activation.
Conclusions:
- Pizotifen acts as a neuroprotective agent against anesthesia-induced cognitive deficits.
- The drug stabilizes dendritic spines and synaptic connections via protein kinase-G and ERK/CREB pathways.
- Pizotifen offers a potential therapeutic strategy to mitigate the harmful effects of anesthesia on brain development.
Abstract:
There is a growing concern worldwide about the potential harmful effects of anesthesia on brain development, based on studies in both humans and animals. In infants, repeated anesthesia exposure is linked to learning disabilities and attention disorders. Similarly, laboratory studies in mice show that neonates exposed to general anesthesia experience long-term cognitive and behavioral impairments. Inhaled anesthetics affect the postsynaptic density (PSD)-95, discs large homolog, and zona occludens-1 (PDZ) domains. The disruption of the synaptic PSD95-PDZ2 domain-mediated protein interactions leads to a loss of spine plasticity and cognitive deficits in juvenile mice. The nitric oxide-mediated protein kinase-G signaling pathway enhances synaptic plasticity also by activating extracellular signal-regulated kinase, which subsequently phosphorylates cAMP-response element binding protein, a crucial transcription factor for memory formation. Exposure to isoflurane or postsynaptic density-95-PDZ2-wildtype peptides results in decreased levels of phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated cAMP-response element binding protein (p-CREB), which are critical for synaptic plasticity and memory formation. Pizotifen treatment after isoflurane or postsynaptic density-95-PDZ2-wildtype peptide exposure in mice prevented decline in p-ERK levels, preserved learning and memory functions at 5 weeks of age, and maintained mushroom spine density at 7 weeks of age. Protein kinase-G activation by components of the nitric oxide signaling pathway leads to the stabilization of dendritic spines and synaptic connections. Concurrently, the ERK/CREB pathway, which is crucial for synaptic plasticity and memory consolidation, is supported and maintained by pizotifen, thereby preventing cognitive deficits caused in response to isoflurane or postsynaptic density-95-PDZ2-wildtype peptide exposure. Activation of ERK signaling cascade by pizotifen helps to prevent cognitive impairment and spine loss in response to postsynaptic density-95-PDZ2 domain disruption.
