AIMS OF THE STUDY

ABSTRACT

INTRODUCTION

Clinical studies with dialytic patients demonstrate that this population is susceptible to alterations of humor, with recurrent depressive episodes or chronic depression. Recent works describe neurodegenerative features in specimens depressive patients, in particular cellular atrophy and cells death in cortical and hippocampal glia and neurons, supporting the neurotrophic theory of depression. This theory is based on the fact that in depressed patient a reduction of the neurotrophin’s levels, in particular the Brain Derived Neurotrophic Factor (BDNF), has been documented. Neurotrophins are small peptides which exert their activity in the cellular trophism, promoting cell differentiation, cellular survival, synaptic plasticity and neurogenesis. To confirm the crucial role of these mediators, it has been demonstrated that the therapy with antidepressant drugs increases neurotrophin’s levels and it is related also with a morfo-anatomical recovery.

AIMS OF THE STUDY

Valuation of the effects of Fluoxetine administration in an experimental model of chronic renal failure in rat.

MATERIALS AND METHODS

30 Wistar female rats have been shared out in three groups: control (C), nephrectomized rats (Nx) and nephrectomized rats treated with Fluoxetine (Nx-F). Surgical 5/6 nephrectomy procedure implys the removal of the right kidney and following excision of the superior and inferior poles of the left kidney. All the animals have been sacrificed at the 12

week.

Animals of the Nx-F group received the drug at a dose of 15 mg/kg for two weeks; during this

period changes in body weights have been recorded and urines have been collected. At the

end of experimental period all animal were sacrificed and samples from serum, liquor,

prefrontal cortex, hippocampus and renal tissue were collected. One half of the kidney has been frozen, the other half was used for paraffin inclusion to perform histological examination. Frozez samples from kidney, cortex and hippocampus, were homogenated for assaying BDNF and nitrotyrosine levels, while in serum and liquor samples we assayed only BDNF levels.

RESULTS

Creatinine clearance in the Nx group was reduced respect the C group (Nx:0,061+/-0,018 vs C:1,103+/-0,108; p<0,01), while in the Nx-F group there was a partial, but meaningful, increasing of such parameter if compared with the Nx group (Nx-F: 0,219+/-0,094 vs Nx:

0,061+/-0,018; p<0,05), even if clearance value remain meaningfully reduced in comparison to the control. Recovery of the renal function was moreover confirmed by the examination of data from proteinuria: in the Nx group it was evident an increase of this parameter in comparison to the C group (Nx: 9,341+/-4,366 mg prot vs C: 3,358+/-1,239 mg prot; p<0,05), while in the Nx-F group no differences were observed (Nx-F: 4,630+/-2,210 mg prot.vs C:

3,358+/-1,239 mg prot).

Histological examination revealed a reduction in pathological morphology and a reduced glomerular expression of Desmin in Nx-F group respect to Nx group.

Renal BDNF levels resulted significanty reduced in nephrectomized rats, regardless of Fluoxetine treatment (Nx-F: 20.932±7.651 pg BDNF/mg prot; Nx: 17.940±9.362 pg BDNF/mg prot vs C: 35.910±14.194 pg BDNF/mg prot; p<0.05), but in the evaluation of the circulating levels of BDNF there were not remarkable variations in the groups C (1433,443+/- 166,108 pg/ml), Nx (1652,793+/-63,050 pg/ml) and Nx-F (1553,521+/-195,495 pg/ml).

Renal nitrotyrosine levels resulted significanty increased in Nx group compared whit Nx-F

and C group (Nx: 4,952+/-1,533 moli/g prot; C: 2,517+/-0,277 moli/g prot; Nx-F: 3,346+/-

1,499 moli/g prot).

On the contrary, BDNF levels in liquor of Nx resulted reduced respect to C group(73,473+/- 34,389 pg BDNF/ml vs 122,169+/-65,360 pg BDNF/ml; p<0.05), while the Nx-F group increased BDNF levels respect the Nx group (Nx-F: 95,605+/-33,148 pg BDNF/ml vs Nx:

73,473+/-34,389 pg BDNF/ml).

In prefrontal cortex, tissutal BDNF levels evidenced a similar reduction in the Nx group if compared to C groups (Nx: 7,842+/-5,588 pg BDNF/mg prot vs C: 12,158+/-6,767 pg BDNF/mg prot; p<0.05), while Nx-F gruop did not differ from C group. In hippocampus, could be observed only and incremental trend in BDNF levels in Nx group (C: 36,616+/- 10,034 pg BDNF/mg prot; Nx: 55,040+/-24,713 pg BDNF/mg prot; Nx-F: 23,147+/-24,37 pg BDNF/mg prot). Finally, cortical (C: 0,166+/-0,140 nmoli/g prot, Nx: 0,160+/-0,134 nmoli/g prot; Nx-F: 0,143+/-0,118 nmoli/g prot) and hippocampal (C: 0,389+/-0,319 nmoli/g prot;

Nx: 0,368+/-0,305 nmoli/g prot; Nx-F: 0,541+/-0,445 nmoli/g prot) nitrotyrosine levels didn’t show any significant variation in the three experimental groups.

CONCLUSIONS Our model of chronic renal failure in the rats demonstrates as the

functional impairment at renal level correlates with alteration of BDNF levels in the CNS,

particolarly in liquor and prefrontal cortex samples. The administration of Fluoxetine induces

not only a BDNF increase in liquor and prefrontal cortex, but also a partial recovery in renal

function and morphology.