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@surgsci.uu.se Sharma HS et al., Uppsala University, Sweden

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. 2011 Mar;9(1):223-35. Sharma HS et al., Uppsala University, Sweden

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. 2006 Sep;124(1-2):211-21. Sharma HS et al., Uppsala University, Sweden

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

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

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

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

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

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

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