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Injections of vehicle, but not cyclosporin A or tacrolimus (FK506), afford neuroprotection following injury in the developing rat brain

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Setkowicz Z. , Guzik R.

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tom 67

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nr 4

EN

Susceptibility of the injured rat brain to seizures depends on the developmental stage at which the injury had been inflicted. Our previous study shows that tacrolimus (FK506) and cyclosporin A (CsA) applied following the injury can also decrease or increase the seizure susceptibility in an age-dependent way. To find possible neuronal substrates of the effects, we examined influences of the agents on the injured brain and on its neuronal population. Rat brains were mechanically injured on postnatal days 6 (P6) or 30 (P30). Twenty minutes and 24 hours following the injury, FK506 or CsA were injected in clinically used pharmaceutical formulations (Prograf® or Sandimmun®, respectively). The brains were fixed on postnatal day 60 and processed for histological examinations. To detect if negative effects of the injury could be abolished by the treatments, we examined the brain weight, the size of the injured region, and the nerve cell density, including the density of calretinin- and parvalbumin-immunopositive cells. We have found that long-term effects of treatments with the FK506- and CsA-containing pharmaceutical formulations were never better than those of the vehicle alone (Cremophor and ethanol mixture). Moreover, the treatments could even amplify negative consequences of the injury alone. It could, therefore, be concluded that all the neuroprotective effects observed in the present study resulted exclusively from the influence of the vehicle alone. These effects of the brain injury and of subsequent treatments performed at different developmental stages were considered as possible determinants of further increase or decrease in susceptibility to seizures observed in adulthood.

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Rola diety w leczeniu chorób neurodegeneracyjnych

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Lipiec O. , Setkowicz Z.

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nr 01-03

3

The brain anatomy imaging after prolonged ketogenic diet feeding in rats

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Gzielo K. , Kielbinski M. , Jasinski K. , Setkowicz Z.

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nr Suppl.1

EN

INTRODUCTION: Ketogenic diet (KD) results in mild to moderate ketosis, which in turn can significantly change the metabolic balance in the brain. The effects of KD are broadly studied in search of potential clinical uses, such as reducing seizure severity in epilepsy, or providing adjunctive therapy for cancer, Alzheimer’s or Parkinson’s disease. The exact mechanism of those putative neuroprotective effects of KD is, however, still poorly understood. AIM(S): Here, we have checked if prolonged ketogenic diet changed beta hydroxy butyrate(BHB) and epididymal fat levels. The crucial thing was to determine how the ketogenic diet affects brain volume and anatomy. METHOD(S): Male Wistar rats were assigned into two experimental groups: one was given KD for 4 months (n=10), the other (n=11) was fed normal laboratory chow (N). After 4 months, rats were sacrificed. Blood samples were collected and BHB levels measured with ELISA. T2-weighed ex vivo images of extracted brains, taken with a 9.4 T magnetic resonance scanner were obtained at the Institute of Nuclear Physics, at XY resolution of 0.025 mm and voxel depth of 0.25 mm. Using a computer-assisted Cavalieri method, the volumes of the entire brain, hippocampus and brainstem structures (midbrain, pons) were estimated. Volumes were compared between groups to show differentially affected regions. Student’s t‑tests was used for statystical analysis. RESULTS: We have observed increased epididymal fat and elevated BHB levels in KD in comparison to the N group (p<0,000001). Additionally we have found a significant reduction in overall pontine volume in the KD group after the 4-month feeding period. CONCLUSIONS: Our results indicate that the prolonged ketogenic feeding was successful in inducing metabolic changes in KD animals. Observed differences in pontine volume in rats fed a ketogenic diet may lead to modification of feeding behavior. These imapairments in food-intake process may be strictly involved with parabrachial structures which are engaged in regulating appetitive behavior. FINANCIAL SUPPORT: Supported by NCS GRANT: UMO-2015/17/B/NZ7/02953.

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Interleukin-1 beta affects the macrophage recruitment and proliferation in the injured brain of 6-day-old rat

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Pawlinski R. , Setkowicz Z. , Malodzinska K. , Janeczko K.

Acta Neurobiologiae Experimentalis

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1999

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tom 59

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nr 4

5

The use of SR - FTIR microspectroscopy for a preliminary biochemical study of the rat hippocampal formation tissue in case of pilocarpine induced epilepsy and neutroprotection with FK- 506

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Dudała J. , Janeczko K. , Setkowicz Z. , Eichert D. , Chwiej J.

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tom Vol. 57, No. 4

615-619

EN

The main aim of the work was the biochemical analysis of the hippocampal formation tissue in the case of epileptic rats treated with the neuroprotective agent FK-506. Three groups of animals were compared: rats with pilocarpine induced seizures treated and non-treated with tacrolimus as well as naive controls. Synchrotron radiation Fourier transform infrared (SR-FTIR) microspectroscopy was used for the biomolecular analysis of studied samples. The measurements were carried out at SISSI beamline of ELETTRA. A Bruker IFS 66v/S interferometer coupled to a Bruker Hyperion 2000 microscope was used. The tissue samples were analyzed in transmission mode with a beam defined by a small aperture and spatial resolution steps of 10 mi m which allowed us to probe the selected cross-line of the sample at cellular resolution. The obtained results enabled to compare the distributions of proteins and lipids in the three hippocampal cellular layers, i.e. in molecular, multiform and granular layers. For epileptic animals both treated and non-treated with FK-506, the tendency for increase of the ratio of the absorbance at around 1548 and 1658 cm-1 (amide II/amide I ratio) was observed, however only for the multiform layer these changes were statistically significant. Similar relation was noticed in case of the ratio of the absorbance at around 1631 and 1658 cm-1. The mentioned results may suggest conformational changes of proteins in the direction of beta-sheet secondary structure. Additionally, a statistically significant increase in the lipid massif and a decrease of the ratio of absorbance at around 2921 and 2958 cm-1 were observed for epileptic animals treated with tacrolimus comparing to the control group.

6

Alterations in brain development in rats treated with immunosuppresant drugs Sandimmune and Prograf and their vehicle components

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Uram L. , Gzielo-Jurek K. , Janeczko K. , Kielbinski M. , Setkowicz Z.

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tom 73

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nr 1

EN

Cyclosporin A and tacrolimus are powerful immunosuppressants used as post-operation medication after allogenic transplantations. Unfortunately, the drugs Sandimmune (cyclosporin A) and Prograf (tacrolimus) exhibit negative side effects. These side effects may be linked not only to the active ingredients themselves, but also to the vehicle used for their delivery – Cremophor EL and/or ethanol. Sandimmune, Prograf, ethanol, Cremophor EL or Cremophor EL with ethanol (i.e. the complete vehicle) in a saline solution were administered to male Wistar rats either on 6th and 7th or 30th and 31st day postnatally. The functional changes in the nervous system elicited by these substances were assessed by observing the intensity of seizures induced by a single i.p. injection of pilocarpine at 60th postnatal day. Brain anatomy was also analyzed by comparing brain mass, lateral ventricle relative area, thickness of cerebral hemisphere wall, relative size of the hippocampus as well as total density of cresyl violet-stained neurons in the cerebral hemisphere walls between control and experimental animals. Our data point to a significant effect of all tested substances on central nervous system development. The greatest effects on seizure severity and brain structure were associated with the complete vehicle. Such effects (although less sever) were also observed for Cremophor EL and ethanol given separately.

7

Effects of FK506 or cyclosporine A on the developing hippocampal formation

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Setkowicz Z. , Radomska K. , Rogoz K. , Uran L. , Janeczko K.

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nr 1

EN

Tacrolimus (FK506) and cyclosporin A (CsA) are immunosupressants widely used in transplantology. They can also protect neurons in several models of brain damage. Prolonged administration of the drugs has many negative neurological side-effects. The effects might depend on the developmental stage but appropriate investigations have been particularly rare. The present study focuses on long-term changes evoked by the drugs in the developing hippocampal formation. Six- and 30-day-old rats (P6s and P30s, respectively) were injected with FK506 or CsA in their pharmaceutical formulas containing a mixture of ethyl alcohol and Cremophor as a vehicle. Controls received the vehicle alone. When the rats were 60-day-old, sizes of their hippocampal formation, densities of calretinin-(CR+), parvalbumin-immunopositive (PV+) neurons and S100β protein-positive (S100β+) astrocytes were assessed. In P6s and P30s treated with CsA in its farmaceutical formula, the size of hippocampal formation was reduced. However, injections of the vehicle alone led to similar effects. In P30s, FK506 decreased the density of CR+ neurons but the vehicle had again the same negative effect. The only signifi cant change in relation to vehicle-treated animals was a decrease in density of PV+ neurons in CsA-treated P30s. In P6s, FK506 dissolved in the vehicle increased the density of S100β+ astrocytes only in relation to naive but not vehicle-treated controls. Longterm effects of FK506 or CsA in their pharmaceutical formulas were mostly negative. Interestingly, they could also be obtained by application of the vehicle alone. Therefore, clinical and experimental effects of FK506 or CsA cannot exclusively be attributed to the drugs themselves abut also to the vehicle which appears to be not biologically neutral.