Press release

OB Pharmaceuticals is developing first-in-class therapeutics for the prevention and management epilepsy. Our lead compound, TD561 shows particular promise in treating drug refractory epilepsy and seizures resulting from brain trauma with high potency and lack of discernible side effects in preclinical studies. “We are proud to be the only company presenting amongst the more than 240 private companies at Biotech Showcase 2018 with a focus on epilepsy therapeutic development,” stated John Poulter, CEO & President, “a disorder of significant unmet medical need.”

Biotech Showcase™, produced by Demy-Colton and EBD Group, is an investor and networking conference devoted to providing private and public biotechnology and life sciences companies with an opportunity to present to, and meet with, investors and pharmaceutical executives in one place during the course of one of the industry's largest annual healthcare investor conferences, J.P. Morgan Annual Healthcare Conference.

Neurobiology of Disease

The piriform cortex (PC) is a three layered phylogenetically old cortical structure (paleocortex) that is part of the limbic system. In addition to olfactory sensation and memory processing (Haberly, 2001), the PC has also been implicated in the development of seizures (Loscher and Ebert, 1996; Racine et al., 1988). As in all cortical networks, the GABAergic interneuron system within the PC is important for the regulation of neuronal excitability and rhythmicity of the neural network, participating in both feed-forward and feedback inhibitory loops (Haberly, 1983; Kelly et al., 2002; Neville and Haberly, 2004). These circuits have been shown to modulate associative long-term potentiation (Kanter and Haberly, 1993) and generate oscillatory activities in the PC (Neville and Haberly, 2003). It has also been shown that the PC is a heterogeneous structure with anatomical differences along the rostro-caudal axis, including differences in layer thickness (Haberly and Price, 1978), the number of interneurons per layers (Haberly et al., 1987; Loscher et al., 1998) as well differences in the laminar distribution/orientation of associational fibers (Haberly and Price, 1978; Luskin and Price, 1983). These morphological traits are thought to reflect different functional roles along the anterior–posterior axis of the PC (Neville and Haberly, 2004). In light of this diverse functionality, the focus on morphological and electrophysiological characteristics of interneuronal subpopulations in the PC has increased. A recent study by Suzuki and Bekkers (2010) has demonstrated in mouse PC a variety of interneuron firing patterns that are similar in many ways to those found in other limbic regions. These included those that fired at high (>50 Hz) and low (b50 Hz) frequencies and those that fired at a constant (non-adapting) or decreasing (adapting) rate. The role of these interneuron firing patterns in the PC has not been examined in the detail that various firing patterns have been studied in other brain regions such as the hippocampus and neocortex.

Frontiers in Neural Circuits

The inhibition of excitatory (pyramidal) neurons directly dampens their activity resulting in a suppression of neural network output. The inhibition of inhibitory cells is more complex. Inhibitory drive is known to gate neural network synchrony, but there is also a widely held view that it may augment excitability by reducing inhibitory cell activity, a process termed disinhibition. Surprisingly, however, disinhibition has never been demonstrated to be an important mechanism that augments or drives the activity of excitatory neurons in a functioning neural circuit. Using voltage sensitive dye imaging (VSDI) we show that 20–80 Hz stimulus trains, β–γ activation, of the olfactory cortex pyramidal cells in layer II leads to a subsequent reduction in inhibitory interneuron activity that augments the efficacy of the initial stimulus. This disinhibition occurs with a lag of about 150–250 ms after the initial excitation of the layer 2 pyramidal cell layer. In addition, activation of the endopiriform nucleus also arises just before the disinhibitory phase with a lag of about 40–80 ms. Preventing the spread of action potentials from layer II stopped the excitation of the endopiriform nucleus, abolished the disinhibitory activity, and reduced the excitation of layer II cells. After the induction of experimental epilepsy the disinhibition was more intense with a concomitant increase in excitatory cell activity. Our observations provide the first evidence of feed forward disinhibition loop that augments excitatory neurotransmission, a mechanism that could play an important role in the development of epileptic seizures.

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