Preclinical treatments for hydrocephalus in juvenile ferrets and rats

• Main Author: Di Curzio, Domenico
• Other Authors: Del Bigio, Marc (Pathology; Human Anatomy and Cell Science)
• Published: BioMed Central 2016
• Subjects: Hydrocephalus; Ferrets; Rats; Brain
• Online Access: http://hdl.handle.net/1993/31647

Hydrocephalus is a common neurological condition characterized by altered cerebrospinal fluid (CSF) flow that results in ventricular expansion due to an accumulation of CSF inside the cranial vault. It is the second most frequent congenital neurologic malformation, but it can manifest at any age, as it is associated with multiple acquired etiologies related to CSF blockage or impaired CSF absorbance. The type and severity of brain damage is dependent on the age of onset, the rate of ventricular enlargement, the magnitude of ventriculomegaly, and how near the impaired brain structure(s) is/are to the cerebral ventricles. The purpose of this thesis was to gain an understanding of potential pharmacological therapies for treating pediatric hydrocephalus that are aimed to supplement commonly used surgical procedures, such as ventricular shunting and endoscopic third ventriculostomy (ETV). In this endeavour, we experimentally induced hydrocephalus by injection of kaolin (aluminum silicate) into the cisterna magna of juvenile rats at 3 weeks age and ferrets at 2 weeks age to mimic the human condition in infants and children. Prior to drug testing, we characterized the ferret model of hydrocephalus and examined the behavioural, brain structural, cellular, and neurobiochemical changes associated with the condition. From there, we treated hydrocephalic rats for 2 weeks with a combination of antioxidant agents, including α-tocopherol, L-ascorbic acid, coenzyme Q10 (CoQ10), reduced glutathione, and reduced lipoic acid to determine if they showed any improvements compared to sham-treated hydrocephalic rats. Afterwards, we used MgSO4 to treat hydrocephalic ferrets for 2 weeks and compared their outcome to sham-treated hydrocephalic ferrets. In both experiments, the pharmacological therapies did not show any significant biochemical and neurological benefits, nor did the animals improve behaviourally compared to sham-treated animals. Overall, it is suggested that therapeutic benefits were not observed in these studies potentially because ventriculomegaly was not severe enough, the route and/or timing of treatment was not maximally effective, or these treatments should be supplemented with surgical interventions to determine their potential synergistic effects, which would be expected to be implemented in the clinical setting. In conclusion, surgical procedures for treating hydrocephalus are rife with complications, which adds to its morbidity and mortality, so it is important to investigate new therapeutic avenues to effectively treat and hopefully cure hydrocephalus one day. === October 2016