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Fluoxetine treatment promotes functional recovery in a rat model of cervical spinal cord injury.

Scali M, Begenisic T, Mainardi M, Milanese M, Bonifacino T, Bonanno G, Sale A, Maffei L - Sci Rep (2013)

Bottom Line: We show that fluoxetine administration markedly improved motor functions compared to controls in several behavioral paradigms.The improved functional effects correlated positively with significant sprouting of intact corticospinal fibers and a modulation of the excitation/inhibition balance.Our results suggest a potential application of fluoxetine treatment as a non invasive therapeutic strategy for SCI-associated neuropathologies.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience CNR, Pisa, Italy.

ABSTRACT
Spinal cord injury (SCI) is a severe condition leading to enduring motor deficits. When lesions are incomplete, promoting spinal cord plasticity might be a useful strategy to elicit functional recovery. Here we investigated whether long-term fluoxetine administration in the drinking water, a treatment recently demonstrated to optimize brain plasticity in several pathological conditions, promotes motor recovery in rats that received a C4 dorsal funiculus crush. We show that fluoxetine administration markedly improved motor functions compared to controls in several behavioral paradigms. The improved functional effects correlated positively with significant sprouting of intact corticospinal fibers and a modulation of the excitation/inhibition balance. Our results suggest a potential application of fluoxetine treatment as a non invasive therapeutic strategy for SCI-associated neuropathologies.

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Spinal cord injury.(a) Histological sagittal sections of CTR-inj (left) and FLX (right) cervical spinal cord. The star indicates the lesion cavity. (b) Quantification of lesion size in CTR-inj and FLX rats as the percentage of max transverse width of the spinal cord. There is no statistical difference between the two groups. Box-whisker plot: the horizontal lines in the box denote the 25th, 50th (median), and 75th percentile values; the small square inside the box represents the mean; error bars denote the 5th and 95th percentile values. X represents max and min values. Scale bar: 1 mm. Abbreviations: D, dorsal; V, ventral; R, rostral; C, caudal.
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f5: Spinal cord injury.(a) Histological sagittal sections of CTR-inj (left) and FLX (right) cervical spinal cord. The star indicates the lesion cavity. (b) Quantification of lesion size in CTR-inj and FLX rats as the percentage of max transverse width of the spinal cord. There is no statistical difference between the two groups. Box-whisker plot: the horizontal lines in the box denote the 25th, 50th (median), and 75th percentile values; the small square inside the box represents the mean; error bars denote the 5th and 95th percentile values. X represents max and min values. Scale bar: 1 mm. Abbreviations: D, dorsal; V, ventral; R, rostral; C, caudal.

Mentions: At the end of the functional evaluation, animals were deeply anesthetized with avertin and placed in a stereotaxic frame. Biotinylated dextran amine (10%, BDA-10,000, Invitrogen) was injected stereotaxically using a glass micropipette (Blaubrand®) at a depth of 1.2 mm at six sites distributed over the sensorimotor cortex (stereotaxic coordinates: AP 0, ML ± 2; AP + 1, ML ± 2; AP 2, ML ± 3). After three weeks rats were sacrificed by chloral hydrate overdose and transcardially perfused with PBS followed by 4% paraformaldehyde in 0.1 M phosphate buffer. Medulla oblongata and C3–C5 spinal cord segments were removed and post-fixed in the same solution at 4°C overnight, followed by 30% sucrose. Tissues were frozen in Tissue-Tek® OCT™ (Sakura, The Netherlands) and transverse 50 μm sections were cut with a cryostat. BDA staining was performed with nickel-enhanced diaminobenzidine (DAB) protocol on slides. The accuracy of the lesion was assessed by the quantification of spared tissue above the central canal in sagittal sections of the C3–C5 spinal blocks (Fig. 5). The mean ratio between lesion depth and transverse spinal cord width was used as lesion size index for each animal. Corticospinal sprouting axons were quantified in the gray matter of the C3–C5 spinal blocks. Five vertical (0.5 mm, 1.5 mm, 2.5 mm, 3.5 mm, 4.5 mm) lines were superimposed on each of at least 10 spinal cord sections (Stereoinvestigator) as reference points for crossing axons starting at the center of the lesion. To correct for variability in BDA uptake by corticospinal neurons in the sensorimotor cortex, we normalized the quantitative data by counting BDA-labeled axons in the main pyramidal tract in three transverse sections of medulla oblongata. A total of 7 CTR-inj and 7 FLX rats were included in this experiment.


Fluoxetine treatment promotes functional recovery in a rat model of cervical spinal cord injury.

Scali M, Begenisic T, Mainardi M, Milanese M, Bonifacino T, Bonanno G, Sale A, Maffei L - Sci Rep (2013)

Spinal cord injury.(a) Histological sagittal sections of CTR-inj (left) and FLX (right) cervical spinal cord. The star indicates the lesion cavity. (b) Quantification of lesion size in CTR-inj and FLX rats as the percentage of max transverse width of the spinal cord. There is no statistical difference between the two groups. Box-whisker plot: the horizontal lines in the box denote the 25th, 50th (median), and 75th percentile values; the small square inside the box represents the mean; error bars denote the 5th and 95th percentile values. X represents max and min values. Scale bar: 1 mm. Abbreviations: D, dorsal; V, ventral; R, rostral; C, caudal.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3713566&req=5

f5: Spinal cord injury.(a) Histological sagittal sections of CTR-inj (left) and FLX (right) cervical spinal cord. The star indicates the lesion cavity. (b) Quantification of lesion size in CTR-inj and FLX rats as the percentage of max transverse width of the spinal cord. There is no statistical difference between the two groups. Box-whisker plot: the horizontal lines in the box denote the 25th, 50th (median), and 75th percentile values; the small square inside the box represents the mean; error bars denote the 5th and 95th percentile values. X represents max and min values. Scale bar: 1 mm. Abbreviations: D, dorsal; V, ventral; R, rostral; C, caudal.
Mentions: At the end of the functional evaluation, animals were deeply anesthetized with avertin and placed in a stereotaxic frame. Biotinylated dextran amine (10%, BDA-10,000, Invitrogen) was injected stereotaxically using a glass micropipette (Blaubrand®) at a depth of 1.2 mm at six sites distributed over the sensorimotor cortex (stereotaxic coordinates: AP 0, ML ± 2; AP + 1, ML ± 2; AP 2, ML ± 3). After three weeks rats were sacrificed by chloral hydrate overdose and transcardially perfused with PBS followed by 4% paraformaldehyde in 0.1 M phosphate buffer. Medulla oblongata and C3–C5 spinal cord segments were removed and post-fixed in the same solution at 4°C overnight, followed by 30% sucrose. Tissues were frozen in Tissue-Tek® OCT™ (Sakura, The Netherlands) and transverse 50 μm sections were cut with a cryostat. BDA staining was performed with nickel-enhanced diaminobenzidine (DAB) protocol on slides. The accuracy of the lesion was assessed by the quantification of spared tissue above the central canal in sagittal sections of the C3–C5 spinal blocks (Fig. 5). The mean ratio between lesion depth and transverse spinal cord width was used as lesion size index for each animal. Corticospinal sprouting axons were quantified in the gray matter of the C3–C5 spinal blocks. Five vertical (0.5 mm, 1.5 mm, 2.5 mm, 3.5 mm, 4.5 mm) lines were superimposed on each of at least 10 spinal cord sections (Stereoinvestigator) as reference points for crossing axons starting at the center of the lesion. To correct for variability in BDA uptake by corticospinal neurons in the sensorimotor cortex, we normalized the quantitative data by counting BDA-labeled axons in the main pyramidal tract in three transverse sections of medulla oblongata. A total of 7 CTR-inj and 7 FLX rats were included in this experiment.

Bottom Line: We show that fluoxetine administration markedly improved motor functions compared to controls in several behavioral paradigms.The improved functional effects correlated positively with significant sprouting of intact corticospinal fibers and a modulation of the excitation/inhibition balance.Our results suggest a potential application of fluoxetine treatment as a non invasive therapeutic strategy for SCI-associated neuropathologies.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience CNR, Pisa, Italy.

ABSTRACT
Spinal cord injury (SCI) is a severe condition leading to enduring motor deficits. When lesions are incomplete, promoting spinal cord plasticity might be a useful strategy to elicit functional recovery. Here we investigated whether long-term fluoxetine administration in the drinking water, a treatment recently demonstrated to optimize brain plasticity in several pathological conditions, promotes motor recovery in rats that received a C4 dorsal funiculus crush. We show that fluoxetine administration markedly improved motor functions compared to controls in several behavioral paradigms. The improved functional effects correlated positively with significant sprouting of intact corticospinal fibers and a modulation of the excitation/inhibition balance. Our results suggest a potential application of fluoxetine treatment as a non invasive therapeutic strategy for SCI-associated neuropathologies.

Show MeSH
Related in: MedlinePlus