1. CEREBROLYSIN ATTENUATES CHRONIC PERIPHERAL NERVE LESION INDUCED SELECTIVE NEURODEGENERATIVE CHANGES IN THE BRAIN. An experimental study using light and electron microscopy in the rat
Hari S Sharma, Dafin F Muresanu, Herbert Mössler,
Torsten Gordh, Aruna Sharma
Dept. Surgical Sciences, Anesthesiology, Uppsala University Hospital, Sweden
Dept. Neurosciences, University of Med & Pharmacy, Cluj-Napoca, Romania
Ever NeuroPharma, Unterach, Austria
Sharma HS et al., Uppsala University, Sweden

2. Cerebrolysin in Chronic Pain & Neurodegeneration
OBJECTIVES
Chronic neuropathic pain induces neurodegeneration?
Chronic pain alters blood-brain barrier (BBB) function?
Ipsilateral or contralateral side of brain damage?
Exogenous supplement of cerebrolysin, a mixture of neurotrophic factors and active peptide fragments could induce neuroprotection?
Sharma HS, Ali SF, Patnaik R, Zimmermann-Meinzingen S, Sharma A, Muresanu DF.Cerebrolysin Attenuates Heat Shock Protein (HSP 72 KD) Expression in the Rat Spinal Cord Following Morphine Dependence and Withdrawal: Possible New Therapy for Pain Management. Curr Neuropharmacol Mar;9(1):
Sharma HS et al., Uppsala University, Sweden

3. Cerebrolysin in Chronic Pain & Neurodegeneration
METHODS & MATERIALS
Left spinal nerve lesion at L 5-6 was performed in rats and allowed to survive 2, 4, 8 and 10 weeks.
Cerebrolysin (Ever NeuroPharma, Austria) was administered intravenously (2.5 ml or 5 ml/kg) once daily starting from day 01 and continued up to 4 weeks.
Structural changes in the brain were examined after 2,4,8 and 10 weeks of nerve lesion in the right and left hippocampus, parietal cerebral cortex and thalamus at Light Microscopy.
Transmission electron microscopy (TEM) was also done on these tissue pieces. Normal rats were used as control.
Gordh T, Chu H, Sharma HS.Spinal nerve lesion alters blood-spinal cord barrier function and activates astrocytes in the rat. Pain Sep;124(1-2):
Sharma HS et al., Uppsala University, Sweden

4. Cerebrolysin in Chronic Pain & Neurodegeneration
RESULTS
Spinal nerve lesion resulted in significant structural changes in the hippocampus, cerebral cortex and thalamus starting from 2 weeks and were most pronounced after 8 weeks.
No further differences in structural changes could be seen in these animals after 10 weeks.
The intensity of structural changes was most pronounced in the contralateral side as compared to the ipsilateral brain regions.
At the ultrastructural level damage to synaptic membranes, vesiculation of neuropil, perivascular astrocytic swelling, deformation of neuronal and endothelial cells were prominent.
Sharma HS et al., Uppsala University, Sweden

5. Cerebrolysin in Chronic Pain & Neurodegeneration
GFAP
8 Weeks after chronic nerve lesion
Activation of astrocytes (GFAP) in the cortex
Damage of nerve cells (Nissl) in the cortex
Albumin leakage in the cortex (BBB disruption)
Nissl
Albumin
All changes were prominent
in the contralateral side after nerve lesion
Contraleteral
Ipsilateral
Sharma HS et al., Uppsala University, Sweden

6. Cerebrolysin in Chronic Pain & Neurodegeneration
RESULTS with Cerebrolysin Treatment
Treatment with low dose of cerebrolysin (2.5 ml/kg) thwarted structural changes in the brain in nerve lesioned rats up to 4 weeks.
High doses of cerebrolysin (5 ml/kg) is needed to reduce morphological changes in the brain seen after 8 and 10 weeks in nerve lesioned animals.
Both contralateral and ipsipateral changes were reduced by cerebrolysin after nerve lesion
Sharma HS et al., Uppsala University, Sweden

7. Cerebrolysin in Chronic Pain & Neurodegeneration
Albumin
Cerebrolysin (CBL) treatment reduces BBB
Leakage of Albumin in the cortex
Reduces astrocytic expression (GFAP)
Activation in the cortex
Attenuates neuronal distortion (Nissl) in
The cortex
GFAP
High doses of CBL is needed to induce
Neuroprotection after nerve lesion upto
8 weeks. Low doses are enough to induce
Brain protection upto 4 weeks after nerve
lesion
Nissl
CBL 2.5 ml/kg
CBL 5 ml/kg
Sharma HS et al., Uppsala University, Sweden

8. Sharma HS et al., Uppsala University, Sweden
Conclusions
Our observations are the first to demonstrate that peripheral spinal nerve lesion could induce selective neurodegeneration in the brain leading to long-term neurological dysfunction.
Cerebrolysin treatment is quite effective in reducing these structural changes in the brain after nerve lesion in a dose and time dependent manner.
These results suggest new roles of cerebrolysin in pain management in future clinical strategies.
Sharma HS et al., Uppsala University, Sweden

9. Sharma HS et al., Uppsala University, Sweden
Generous Support
European Office of Aerospace Research & Development (EOARD), London, UK
Wright Patterson Air Force Base, US Air Force Research Laboratory, Dayton, OH, USA
Ever Neuro Pharma, Unterach, Austria
Amity Science & Research Foundation, New Delhi, India
National Centre for Toxicological Research/NCTR, US Food & Drug Administration (FDA), Jefferson, AR, USA
Swedish Medical Research Council (MFR), Stockholm, Sweden
University Grants Commission, Govt. Of India, New Delhi, India
The authors have no conflict of interests with any agency or entitiy mentioned above
Sharma HS et al., Uppsala University, Sweden

10. This is a presentation from Uppsala University