Excessive and prolonged lipolysis in adipose tissue of dairy cows is a major risk factor for clinical ketosis (CK). This metabolic disease is common in postpartum cows when fatty acid lipolysis is used as an energy substrate to compensate for negative energy balance. Lipolysis in cattle can be induced by both conventional (hormone-induced) and inflammatory pathways. Current treatments for CK focus on improving blood glucose (eg, oral propylene glycol [PG], or (i.v.) dextrose).However, these treatments do not inhibit conventional lipolytic and inflammatory pathways. Niacin (NIA) can reduce the activation of the canonical pathway. Blocking inflammatory responses with cyclooxygenase inhibitors such as flunixin meglumine (FM) can inhibit inflammatory lipolytic activity. The aim of this study was to determine the effects of NIA and FM in the standard propylene glycol treatment for postpartum clinical ketosis on the concentrations of ketone bodies.
A study (randomized in 4 groups, parallel and separate on multiple Jersey cows (80 heads)) was conducted in an industrial dairy farm during a period of 7 months. Eligible cows had clinical signs of ketosis (lethargy, decreased appetite and milk production) and hyperketonemia (blood β-hydroxybutyrate [BHB] ≥1.2 mmol/L). Cows with clinical ketosis were randomly assigned to one of three groups, in which the first group received 310 g of PG orally once a day for 5 days. The second group received PG for 5 days plus 24 g NIA orally once a day for 3 days (PGNIA) and the third group received PG for 5 days plus NIA for 3 days + 1.1 mg/kg, intravenous FM, once per day for 3 days (PGNIAFM). The control group consisted of cows that were clinically healthy (HC; no treatment; BHB <1.2 mmol/L, 27 cows) and were matched to all 3 groups in terms of abdomen and lactation days. Cows were sampled on the start day (d 0), 3, 7 and 14 to evaluate ketone bodies and metabolic and inflammatory biomarkers in blood.Effects of treatment, sampling day and their interactions were evaluated using mixed effects models. Logistic regression was used to calculate the odds ratio (OR) of returning to normoctonemia (BHB <1.2 mmol/L).
Compared to the control group, cows with clinical ketosis showed lower blood concentrations of dyslipidemia markers, including non-esterified fatty acids (NEFA) and BHB, and lower glucose and insulin levels. Cows with clinical ketosis also had increased levels of biomarkers of pain, inflammation, including serum lipopolysaccharide-binding protein, haptoglobin, and amyloid A, and proinflammatory cytokines IL-4, MCP-1, MIP-1α, and TNFα. Importantly, 72.2% of CK cows were endotoxemic and had higher circulating bacterial DNA compared to the control group. On day 7, the highest percentage of cows with normoctonemia was in PGNIAFM = 87.5%, compared to PG = 58.33%, and PGNIA = 62.5%. On day 7, the ORs for normoctonemia in PGNIAFM cows were 1.5 and 1.4, relative to PG and PGNIA, respectively. On days 3, 7 and 14, PGNIAFM cows had the lowest values of BHB (PG = 1.36; PGNIA = 1.24; PGNIAFM = 0.13 ± 0.89 mmol/L), NEFA (PG = 0.58; PGNIA = 0.59; PGNIAFM = 0.02 mmol/L) and presented acute phase proteins. Cows on PGNIAFM also presented the highest blood glucose increases across time points and insulin by day 7.
These data provide evidence that bacteremia or endotoxemia, systemic inflammation, and pain may play an important role in the pathogenesis of clinical ketosis. Additionally, targeting lipolysis and inflammation with OUR and FM .
