br Conclusions Several lines of

Conclusions Several lines of evidence have been established, which support the adenosine kinase hypothesis of epileptogenesis, which is based on a sequence of events leading from acute glycyrrhizic acid injury to initial downregulation of ADK, rise in extracellular adenosine, changes in astrocytic adenosine receptor expression, increased proliferation and hypertrophy of astrocytes (i.e. astrogliosis), astrogliotic upregulation of ADK, reduction of the endogenous anticonvulsant adenosine, and finally to the generation of spontaneous seizures: (i) ADK is the key enzyme for regulation of the endogenous anticonvulsant adenosine (Boison, 2006). (ii) In adult brain, ADK is predominantly expressed in astrocytes (Studer et al., 2006). (iii) Astrogliosis is a hallmark of epilepsy (Duffy and MacVicar, 1999, Rothstein et al., 1996, Tashiro et al., 2002). (iv) ADK is upregulated in astrogliotic hippocampus, contributing to spontaneous seizures via reduction of the adenosine tone (Gouder et al., 2004). (v) Transgenic overexpression of ADK leads to spontaneous seizures (Fedele et al., 2005) and increased neuronal vulnerability (Pignataro et al., 2007b). (vi) Pharmacological inhibition of ADK prevents otherwise pharmacoresistant seizures in mice (Gouder et al., 2003, Gouder et al., 2004). (vii) Mice with a forebrain selective reduction of Adk are resistant to epileptogenesis (Li et al., 2008). (viii) Augmentation of the adenosine system by brain implants of stem cells engineered to release adenosine has the potential to prevent epileptogenesis in at least two animal models (rat kindling model and mouse intraamygdaloid KA model).
Acknowledgments
Introduction Age-related hearing loss (ARHL), or presbyacusis, is the most common sensory deficit (Morton, 1991). It is characterised by a decline in hearing sensitivity and speech discrimination, delayed central processing of acoustic information, and impaired localisation of sound sources (Gates and Mills, 2005). Various cochlear pathologies related to ARHL have been observed, including loss of sensory hair cells and spiral ganglion neurones, and degeneration of secretory and supporting tissues (stria vascularis and spiral ligament) that are responsible for maintenance of electrochemical homeostasis of cochlear fluids (Schuknecht and Gacek, 1993). Mechanical changes to the basilar membrane have also been proposed to explain the deterioration in the audiogram (Schuknecht and Gacek, 1993). Secondary changes in the central auditory pathways also contribute to the hearing deficits (Syka, 2002). Multiple mechanisms have been proposed for age-related cochlear degeneration, and it appears that both genetic and environmental factors play a role (Van Eyken et al., 2007). A dominant theory is that accumulated oxidative stress causes cochlear damage (Seidman et al., 1999, Staecker et al., 2001, Jiang et al., 2007), possibly as a consequence of impaired blood flow (Dai et al., 2004) or environmental factors such as excessive noise (Ohlemiller et al., 2000a). This results in membrane and mitochondrial DNA damage in cochlear tissues leading to cell death and hearing loss (Fischel-Ghodsian et al., 1997, Ueda et al., 1998, Seidman et al., 1999, Fischel-Ghodsian, 2003, Pickles, 2004, Yin et al., 2007, Niu et al., 2007). Much of our understanding of the mechanisms of ARHL comes from animal models (Zheng et al., 1999, Ohlemiller, 2006, Bielefeld et al., 2008). The variance seen in susceptibility to hearing loss both within and between genetic models is similar to that seen in susceptibility to both noise- and age-related hearing loss in humans, which may include individual differences in resistance to environmental stress (Duvdevany and Furst, 2007). Inbred mice often show early onset ARHL (Zheng et al., 1999), and the C57BL/6J mouse is the most established model of accelerated ARHL exhibiting behavioural and functional changes similar to those in the ageing human ear (Prosen et al., 2003, Francis et al., 2003). Akin to humans, the hearing loss progresses from the high to low frequencies and the damage comprises loss of sensory cells and neurons starting in the base and progressing to the apex of the cochlea (Spongr et al., 1997, Bartolomé et al., 2002). Other studies have shown that cochlear pathology also includes degeneration of the stria vascularis and fibrocytes of the spiral ligament (Ichimiya et al., 2000, Hequembourg and Liberman, 2001), reinforcing the utility of the C57BL/6J mouse as a model of mixed presbyacusis in humans (Ohlemiller, 2006). The C57BL/6J mouse is also more susceptible to the damaging effects of noise exposure, ototoxic drugs and hypoxia (Ohlemiller et al., 2000a, Ohlemiller, 2006), suggesting diminished protective or reparative processes compared to mouse strains that do not show early onset ARHL.