PK 11195 attenuates kainic acid‐induced seizures and alterations in peripheral‐type benzodiazepine receptor (PBR) protein components in the rat brain

Abstract

Peripheral-type benzodiazepine receptors (PBR) are located in glial cells in the brain and in peripheral tissues. Mitochondria form the primary location for PBR. Functional PBR appear to require at least three components: an isoquinoline binding protein, a voltage-dependent anion channel, and an adenine nucleotide carrier. In the present study, rats received intraperitoneal kainic acid injections, which are known to cause seizures, neurodegeneration, hyperactivity, gliosis, and a fivefold increase in PBR ligand binding density in the hippocampus. In the forebrain of control rats, hippocampal voltagedependent anion channel and adenine nucleotide carrier abundance was relatively low, while isoquinoline binding protein abundance did not differ between hippocampus and the rest of the forebrain. One week after kainic acid injection, isoquinoline binding protein abundance was increased more than 20-fold in the hippocampal mitochondrial fraction. No significant changes were detected regarding hippocampal voltage-dependent anion channel and adenine nucleotide carrier abundance. Pre-treatment with the isoquinoline PK11195, a specific PBR ligand, attenuated the occurrence of seizures, hyperactivity, and increases in isoquinoline binding protein levels in the hippocampus, which usually follow kainic acid application. These data suggest that isoquinoline binding protein may be involved in these effects of kainic acid injections.

The 18 kDa Translocator Protein as a Potential Participant in Atherosclerosis

“…Thus, it has been suggested that TSPO in glia may play a role in neurodegenerative processes and brain damage. In animal studies, both PK 11195 and Ro5-4864 presented neuroprotective effects against brain injury, which have been suggested to involve neurosteroid activation (Veenman et al, 2002;Veenman & Gavish, 2006Soustiel et al, 2008). Alternatively, it has been suggested that enhanced levels of TSPO in neural cells (due to damage, disease, etc.)…”

“…This topic has arisen from the electron microscopic observation that the 18 kDa TSPO protein was organized in clusters of 2-7 molecules on Leydig cell mitochondrial membranes (Papadopoulos et al, 1997). It was also suggested that free TSPO (meaning not in complex with VDAC and ANT) may be present in mitochondrial membranes (Veenman et al, 2002;Liu et al, 2003). This claim further takes into consideration that modulation of steroidogenesis only requires a mitochondrial channel that is www.intechopen.com formed by the mitochondrial TSPO, without participation of VDAC and ANT (Papadopoulos et al, 2006).…”

“…TSPO are found throughout the animal kingdom, including insects, mollusks, pisces, amphibians, aves and mammals (Peterson et al, 1988;Veenman et al, 2007), yet have not been found in reptiles as to date (Bolger et al, 1986). Widely expressed throughout the body, TSPO exhibit different patterns of tissue specific expression (Golani et al, 2001;Veenman et al, 2002). In vivo studies showed the rank order of TSPO binding density in rats to be adrenal >> kidney ~ heart ~ testis ~ ovary >> liver ~ brain (Awad & Gavish, 1987;Gavish et al, 1999).…”

“…VDAC and ANT are considered to form the core components of the mitochondrial permeability transition pore (mPTP) (Galiegue et al, 2003). The ratio of TSPO to VDAC and ANT appears to be tissue-and treatment-dependent (Golani et al, 2001;Veenman et al, 2002). The mitochondrial location of the TSPO is interesting in relation to cardiovascular diseases, as it is well known that mitochondria are a main source of cellular ROS (Lenaz, 1998).…”

Microglial positron emission tomography (PET) imaging in epilepsy: Applications, opportunities and pitfalls

“…For example, pre-treatment of rats with PK11195 attenuates the occurrence of seizures in a kainic acid-induced model of seizures [25], and another TSPO-selective ligand, XBD173, induces neurosteroid synthesis and is anxiolytic in humans without benzodiazepine-like side effects [26].…”