Measurement of Neutrophil Gelatinase-Associated Lipocalin Concentration in Canine Cerebrospinal Fluid and Serum and Its Involvement in Neuroinflammation

Abstract

Neutrophil gelatinase-associated Lipocalin (NGAL) is a glycoprotein involved in inflammation acting as an acute phase protein and chemokine as well as a regulator of iron homeostasis. NGAL has been shown to be upregulated in experimental autoimmune encephalomyelitis (EAE) in mice. Increased NGAL concentration in cerebrospinal fluid (CSF) and expression in central nervous system (CNS) has been described in human neuroinflammatory disease such as multiple sclerosis and neuropsychiatric lupus as well as in bacterial meningitis. We aimed to investigate involvement of NGAL in spontaneous canine neuroinflammation as a potential large animal model for immune- mediated neurological disorders. A commercially available Enzyme-linked Immunosorbent Assay (ELISA) for detection of canine NGAL was validated for use in canine CSF. Concentration in CSF and serum of canine patients suffering from steroid- responsive meningitis- arteriitis (SRMA), Meningoencephalitis of unknown origin (MUO), different non- inflammatory CNS disease and control dogs were compared. Relationship between NGAL concentration in CSF and serum and inflammatory parameters in CSF and blood (IgA concentration, total nucleated cell count (TNCC), protein content) as well as association with erythrocytes in CSF, duration of illness, plasma creatinine and urinary leucocytes were evaluated. In dogs with SRMA and MUO, CSF concentration of NGAL was significantly higher than in dogs with idiopathic epilepsy, compressive myelopathy, intracranial neoplasia and SRMA in remission (p < 0.0001). Patients with acute SRMA had significantly higher levels of NGAL in CSF than neurologically normal controls (p < 0.0001). Serum NGAL concentrations were significantly higher in dogs with SRMA than in patients with myelopathy and intracranial neoplasia (p < 0.0001). NGAL levels in CSF were strongly positively associated with IgA concentration (rSpear= 0.60116, p < 0.0001), TNCC (rSpear= 0.65746, p < 0.0001) and protein content (rSpear= 0.73353, p < 0.0001) in CSF. It can be measured in CSF of healthy and diseased dogs. Higher concentrations in canine patients with SRMA as well as positive association with TNCC in CSF suggest an involvement in pro-inflammatory pathways and chemotaxis in SRMA. High serum levels of NGAL in serum of SRMA patients in different stages of disease might reflect the systemic character of the disease.

Detection of Extracellular Traps in Canine Steroid-Responsive Meningitis-Arteritis

“…Furthermore, elevated immunoglobulin A levels in serum and CSF serve as diagnostic tool ( 44 , 52 ). Levels of acute phase proteins such as C-reactive protein, serum amyloid A, haptoglobin ( 53 ), or neutrophil gelatinase-associated lipocalin ( 54 ) are elevated in the acute disease episode compared to non-inflammatory neurological diseases. Especially, CRP is used as a remission and therapy monitoring marker ( 55 ).…”

Oxidative Stress Markers in Cerebrospinal Fluid of Newly Diagnosed Multiple Sclerosis Patients and Their Link to Iron Deposition and Atrophy

“…Neutrophil Gelatinase-Associated Lipocalin (NGAL, also known as Lipocalin-2, or LCN2) is involved in several inflammatory pathways [ 28 ]. Its increased concentration in CSF is reported in patients with MS, especially those with secondary progressive MS and primary progressive MS compared to RRMS [ 8 ].…”

Differential Performance of Neutrophil Gelatinase-Associated Lipocalin and Cystatin C to Predict Ischemic Stroke

“…Many studies have found that NGAL can also be used as a marker of neuroin ammation and related behavioral dysfunction [15,16]. The increase of NGAL in brain tissue can aggravate amyloid-β-induced toxicity, leading to neurodegenerative changes in the brainstem nucleus [17]. Iron chelator has the potential to improve neurodegenerative changes and treat central nervous system diseases, but its neuroprotective effect may be related to patient's NGAL level [18].…”