Gadolinium retention in the ischemic cerebrum: Implications for pain, neuron loss, and neurological deficits

Purpose To investigate the effects of gadolinium (Gd) retention of macrocyclic (gadobutrol) or linear (gadopentetate) Gd‐based contrast agents (GBCAs) on neuron loss, neurological deficits, and sensory behavior in mice with or without stroke. Methods Ninety C57BL/6 mice underwent sham ( n = 36) or transient middle cerebral artery occlusion (tMCAO) ( n = 54) surgery and then received intraperitoneal injections of 5.0 mmol/kg gadobutrol, 5.0 mmol/kg gadopentetate or saline (10 ml/kg/administration) per day for 3 consecutive days. The Gd concentration in the ischemic cerebrum was quantified by inductively coupled plasma mass spectrometry on Day 1 and Day 28 after the last injection (post‐injection, p. i.). Neuron loss, glia activation and neurological deficits were assessed on Day 1 and 28 p. i. Sensory behavior was also assessed on Day 28 p. i. Results Gd concentrations were higher in the brains of tMCAO mice than in those of sham mice on Days 1 p. i. of both GBCAs (gadobutrol, p < 0.05; gadopentetate, p < 0.001) and 28 p. i of gadopentetate. ( p < 0.001). Sham or tMCAO mice injected with GBCAs showed no significant difference in neuron loss, glia activation, neurological deficits, brain atrophy, or hippocampus‐dependent memory (all p > 0.05). Both gadobutrol and gadopentetate induced mechanical and heat hyperalgesia in sham mice (all p < 0.05). However, mechanical hyperalgesia but rather heat hyperalgesia was found in tMCAO mice with the highest force tested (1.0 g) and statistically significant in both paws (right and left) with gadopentetate only ( p < 0.05). Conclusions Neither gadobutrol nor gadopentetate worsened neuron loss, glia activation, brain atrophy, neurological deficits, or hippocampus‐dependent memory after tMCAO. However, GBCA administration induced mechanical hyperalgesia in sham and tMCAO mice although in the same level, which may be an important consideration for patients with central post‐stroke pain and those who are sensitive to pain and about to receive multiple GBCA administrations.