Pro-inflammatory effects of placebo neurosurgery in rats: age-related features

Abstract

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most prevalent neurodegenerative diseases, affecting millions of people globally and causing significant disability and mortality. Animal models are the final step in completing preclinical studies and the most appropriate approach for gaining a thorough understanding of disease pathophysiology. Modeling of idiopathic AD and PD in rodents requires stereotactic injections of disease‑triggering substances. The placebo surgery group is an integral component of the design of these experiments in order to diminish study bias as a result of animal stress and non‑specific surgical impact. Inflammation is the most commonly reported non‑specific post‑surgery phenomenon, which can manifest in different ways in animals of different ages used in these experiments.

Objective — to compare the long‑term pro‑inflammatory effects of placebo surgery, commonly employed for PD and AD modeling, in rats of different ages.

Materials and methods. Adult male Wistar rats aged 4 and 14 months were used in the study. The placebo surgery consisted of a stereotactic unilateral intracerebral infusion of buffer solution. Before the placebo surgery, animals were anaesthetized using ketamine or xylazine administered intraperitoneally. Intact animals of both ages were used as a control. The evaluation of pro‑inflammatory effects of placebo surgery was conducted using biomarkers of local and systemic inflammation: metabolic polarization of phagocytes (microglia, peripheral blood cells), C‑reactive protein (CRP) plasma level, and systemic inflammation indexes calculated from the hemogram study.

Results. In young lesioned animals, a pronounced pro‑inflammatory functional shift of microglia and signs of the resolution of systemic inflammation (an anti‑inflammatory skew of circulating phagocyte metabolism as compared to age‑matched intact controls) were observed in the long term after the placebo neurosurgery. In old intact animals, hematological and immunological markers of low‑grade systemic inflammation were observed. In lesioned old rats, residual neuroinflammation along with pronounced systemic inflammatory responses (leukocytosis, substantially increased SIRI and SII values, pro‑inflammatory metabolic shift of peripheral blood phagocytes as compared to age‑matched intact controls) were registered.

Conclusions. The effects of placebo neurosurgical manipulations in rats depend on age. Meta‑inflammation inherent to aged rats is aggravated by non‑specific post‑surgery inflammation, leading to pronounced, persistent systemic inflammatory responses.