Dose and Time Related Neuroprotective effects of Cerebrolysin in Concussive Head Injury

Concussive head injury (CHI) is a serious clinical problem especially in military and sports personnel causing pronounced behavioral, cognitive and neuropathological consequences culminating in deterioration of quality of life of the victims.  Military personnel are suffering from a variety of concussive injuries either caused by roadside bomb explosion, missile explosion or blast injuries as well as a direct insult on their head using blunt objects. Whereas, sports personnel can get concussive injury in football using head to receive the ball or in other sports where accidental blunt head injury may occur after fall or related head trauma. Research carried out in these areas suggests that there are no subtle differences between blast or sports injury induced concussion. The basic mechanisms of concussion injury appear to be very similar in such situations i.e., blast or sports injury. Whereas, other causes of CHI includes motor vehicle accidents, street fighting or blunt head injury from any object at home or at work place. Thus, CHI causing lifetime disabilities leading to a huge financial burden on the society. Accordingly, new efforts are needed to explore novel therapeutic strategies to treat CHI cases to enhance quality of life of CHI victims. Since CHI is well known to alter endogenous balance of amino acid neurotransmitters in the central nervous system (CNS), a possibility exists that restoring the balance in CHI using therapeutic measures could benefit the patients. In this investigation we used a multimodal drug Cerebrolysin (Ever NeuroPharma, Austria) that is a well balanced composition of several neurotrophic factors and active peptide fragments in exploring its effects on CHI induced alterations in key excitatory (Glutamate, Aspartate) and inhibitory (GABA, Glycine) amino acids in the CNS in relation brain pathology in a dose and time related manner. CHI was produced in anesthetized rats by dropping a weight of 114.6 g over the right exposed parietal skull from a distance of 20 cm height (0.224 N impact) and blood-brain barrier (BBB), brain edema, neuronal injuries and behavioral dysfunctions were measured 8, 24, 48 and 72 h after injury. Cerebrolysin (CBL) was administered (2.5, 5, 10 or 20 ml/kg, i.v.) after 4 to 24 h following injury. Our observations show that CBL induced a dose dependent neuroprotection in CHI (5 to 10 ml/kg) and also improved behavioral functions. Interestingly when CBL is delivered through TiO2 nanowires superior neuroprotective effects were observed in CHI even at a lower doses (2.5 to 5 ml/kg). These observations are the first to demonstrate that CBL is effectively capable to attenuate CHI induced brain pathology and behavioral disturbances in a dose dependent manner, not reported earlier.