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Jelena Lazovic

Publications and source records attributed to Jelena Lazovic.

5 recordsLinked to original sources
PubMed2006

A diet-induced mouse model for glutaric aciduria type I.

In the autosomal recessive human disease, glutaric aciduria type I (GA-1), glutaryl-CoA dehydrogenase (GCDH) deficiency disrupts the mitochondrial catabolism of lysine and tryptophan. Affected individuals accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in the serum and often suffer acute striatal injury in childhood. Prior attempts to produce selective striatal vulnerability in an animal model have been unsuccessful. We hypothesized that acute striatal injury may be induced in GCDH-deficient (Gcdh-/-) mice by elevated dietary protein and lysine. Here, we show that high protein diets are lethal to 4-week-old and 8-week-old Gcdh-/- mice within 2-3 days and 7-8 days, respectively. High lysine alone resulted in vasogenic oedema and blood-brain barrier breakdown within the striatum, associated with serum and tissue GA accumulation, neuronal loss, haemorrhage, paralysis, seizures and death in 75% of 4-week-old Gcdh-/- mice after 3-12 days. In contrast, most 8-week-old Gcdh-/- mice survived on high lysine, but developed white matter lesions, reactive astrocytes and neuronal loss after 6 weeks. Thus, the Gcdh-/- mouse exposed to high protein or lysine may be a useful model of human GA-1 including developmentally dependent striatal vulnerability.

Amino Acid Metabolism, Inborn Errors↗
PubMed2005

Neuroinflammation and both cytotoxic and vasogenic edema are reduced in interleukin-1 type 1 receptor-deficient mice conferring neuroprotection.

BACKGROUND AND PURPOSE: Interleukin-1 (IL-1) is a proinflammatory cytokine implicated in multiple neurodegenerative diseases, including stroke. However, to date, there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. We hypothesized that abrogating IL-1 type 1 receptor (IL-1R1) signaling would reduce edema, chemokine expression, and leukocyte infiltration; lower levels of iNOS; and, consequently, decrease free radical damage after mild hypoxia/ischemia (H/I), thus preserving brain cells. METHODS: IL-1R1 null mice and wild-type mice were subjected to a mild H/I insult. MRI was used to measure the area affected at 30 minutes and 48 hours after H/I. An RNAse protection assay was used to evaluate changes in chemokine mRNA expression. RT-PCR was used to assess inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase mRNA levels. Immunohistochemistry was used to assess leukocyte infiltration. Western blots were used to assess iNOS and glutamate aspartate transporter protein levels. RESULTS: IL-1R1 null mice had reduced cytotoxic and vasogenic edema. The volume of hyperintense signal on T2-weighted images was reduced on average by 90% at 48 hours after H/I. The induction of multiple chemokine mRNAs was significantly reduced in IL-1R1 null mice compared with wild-type mice at 18 and 72 hours after H/I, which correlated with fewer infiltrating CD3+ leukocytes. Levels of iNOS protein and mRNA (but not glutamate aspartate transporter) were significantly reduced in the IL-1R1 mouse brain. CONCLUSIONS: These findings indicate that abrogating IL-1R1 signaling could protect brain cells subsequent to a mild stroke by reducing edema and immune cell recruitment, as well as by limiting iNOS-mediated free radical damage.

Amino Acid Transport System X-AG↗
PubMed2005

Hexagonal zero mode TEM coil: a single-channel coil design for imaging multiple small animals.

A novel hexagonal coil design for simultaneous imaging of multiple small animals is presented. The design is based on a coaxial cavity and utilizes the magnetic field formed between two coaxial conductors with hexagonal cross-sections. An analytical solution describing the B(1) field between conductors of the hexagonal coil was found from the Biot-Savart law. Both experimental results and analytical calculations showed a variation in the B(1) field within the imaging region of less than 10%. Numerical calculations predicted approximately 35% improvement in B(1) field homogeneity with the hexagonal coil design compared to a cylindrical coaxial cavity design. The experimentally-measured signal-to-noise ratio (SNR) of the hexagonal coil loaded with six 50-mM phantoms was only 4-5% lower than that of a single parallel plate resonator loaded with one phantom. In vivo spin-echo (SE) images of six 7-day-old rat pups acquired simultaneously demonstrated sufficient SNR for microimaging. The construction scheme of the coil, simple methods for tuning and matching, and an anesthesia device and animal holder designed for the coil are described. The hexagonal coil design utilizes a single receiver and allows for simultaneous imaging of six small animals with no significant compromise in SNR.

Animals↗
PubMed2005

Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury.

Excessive inflammation has been implicated in the progressive neurodegeneration that occurs in multiple neurological diseases, including cerebral ischemia, and elevated levels of the proinflammatory cytokine interleukin-1 (IL-1) have been shown to exacerbate brain damage, whereas diminishing IL-1 levels limits the extent of injury. However, to date there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. Because we have previously demonstrated that signaling through the IL-1 type 1 receptor (IL-1R1) is necessary for microglial activation and because results from other studies have implicated microglia as effectors of neurodegeneration, we hypothesized that inactivating the IL-1R1 would decrease the extent of damage caused by a hypoxic-ischemic (H/I) insult. It is shown that a mild insult initiates progressive neurodegeneration that leads to cystic infarcts, which can be prevented by inactivating the IL-1R1. The IL-1R1 null mice also show preserved sensorimotor function at 1 month's recovery. The mild insult induces multiple proinflammatory cytokines and activates microglia, and these responses are dramatically curtailed in mice lacking the IL-1R1. Importantly, the neuroinflammation precedes the progressive enlargement of the infarct, suggesting that the inflammation is causal rather than a consequence of the brain damage. These findings show that abrogating the inflammation consequent to a mild H/I insult will prevent brain damage and preserve neurological function. Additionally, these data incriminate the IL-1R1 as a master proinflammatory cytokine receptor.

Animals↗