The Patel Lab

Journal of Neuroscience
Vol. 32, Issue 33
15 Aug 2012

Cover legend: The hydrophilic domain of rat mitochondrial electron transport chain complex I is involved in the production of cellular ATP. During epileptogenesis, arginine 76 (orange spheres) of the 75 kDa subunit (purple ribbon) is irreversibly modified by carbonylation, leading to decreased complex I activity. This residue is located at the interaction interface between the 75 kDa subunit and the 51 kDa subunit (green ribbons), proximal to the NADH binding site (red sticks) and the sulfur-iron center involved in the initial transfer of electrons into the chain (yellow and purple sticks). For more information, see the article by Ryan et al. (pages 11250–11258​).

Summary: Dr. Patel’s early work addressed a fundamental question in the field of neuroscience; namely, how does excessive glutamate neurotransmission induce excitotoxic cell death? She demonstrated a role for intracellular superoxide radicals in excitotoxic cell death emphasizing the overlapping roles of oxidative stress and excitotoxic injury, two independent pathological mechanisms common to diverse neurological disorders (Patel et al., Neuron 16:345-355, 1996). This discovery led to the overarching theme of her laboratory, which is to understand the role of reactive species and metabolic mechanisms in neuronal disorders such as epilepsy.

Research Areas. The overarching theme of the Patel laboratory is to understand the role of redox processes and metabolic mechanisms in epilepsy, aging and toxicant-induced brain injury. Using biochemical, metabolic, transgenic and translational approaches, research in the laboratory is focused on three major areas: a) understanding the mechanisms of redox and metabolic dysfunction in response to epileptogenic insults, b) developing neuroprotective drugs and therapies and c) identifying metabolic targets of ketogenic diets. The following sections describe the major research areas in the Patel lab.

Defining the role of oxidative stress and metabolic dysfunction in epilepsy and its comorbidities. Epilepsy is a recent addition to the diverse array of acute and chronic neurological disorders in which the role of oxidative stress and mitochondrial dysfunction is rapidly emerging. Our research has been pioneering and instrumental in defining the role of redox and metabolic mechanisms in the pathogenesis of epilepsy and its comorbidities. The laboratory identified subcellular sources of reactive species (RS), their temporal occurrence and functional impact in animal models of temporal lobe epilepsy (TLE). Our focus on mitochondria arose from investigation of subcellular sources of seizure-induced RS, which indicated a disproportionate contribution of mitochondria. Work from our laboratory has demonstrated increased production of mitochondrial reactive oxygen species (mtROS) and persistent depletion of glutathione during epileptogenesis in two animal models. We demonstrated for the first time an oxidative post-translational modification via carbonylation of the 75kDa subunit of CI in experimental TLE. A functional consequence of oxidative damage to mitochondria in epilepsy is a bioenergetics decline, which can increase neuronal excitability. We recently demonstrated that increased ROS indeed result in deficits of mitochondrial respiration in experimental TLE. Finally, we showed that mitochondrial oxidative stress results in mitochondrial dysfunction and neuronal death which contributes to cognitive deficits associated with chronic epilepsy. Our studies suggest redox and mitochondrial pathways as novel therapeutic approaches for modifying acquired epilepsy and associated cognitive deficits. A recent collaboration with Dr. Scott Baraban’s laboratory identified metabolic deficits in genetic models of epilepsy, notably Dravet’s syndrome.

Delineating mitochondrial mechanisms of oxidative brain injury. Mitochondrial oxidative stress is well known to play a pathogenic role in neuronal disorders. However, the mechanisms by which ROS produce damage are incompletely understood. Our research has demonstrated that that superoxide toxicity via oxidative inactivation of mitochondrial aconitase contributes to neuronal death in animal models of neurodegeneration. Studies in the laboratory have identified a novel pool of mitochondrial iron that correlates with mitochondrial aconitase inactivation in brain injury models. We identified mitochondrial complex III as a major source of ROS via redox cycling agents. These studies led to the novel discovery that brain mitochondria consume hydrogen peroxide (H2O2) in a substrate-dependent manner via the thioredoxin/peroxiredoxin pathway linked by mitochondrial nicotinamide transhydrogenase activity. ​​​​

Patel Receives Javits Award for her Body of Research on Neuroscience

When Manisha Patel, PhD, was notified she had been awarded the Javits Award in Neuroscience, she was honored. The Javits Award is a conditional, seven-year research grant given to scientists for their superior competence and outstanding productivity. Dr. Patel received her award for her ongoing work in neuroscience, researching the role of energy and oxidative stress in epilepsy. Her current work builds upon over twenty years of research in her own lab to identify the oxidation-reduction and metabolic mechanisms of seizure-induced brain injury. The project aims to test a new hypothesis  and could help to develop novel metabolism-based therapies for epilepsy.

Manisha Patel Installed as President of the American Epilepsy Society

Pharmaceutical Sciences Professor Manisha Patel, PhD, begins her term as president of the American Epilepsy Society (AES) at the conclusion of the Society’s annual meeting in Nashville, Dec. 2- 6. A medical and scientific society of 4,700 members, the AES is dedicated to advancing research and education for preventing, treating and curing epilepsy. Founded in 1946, AES is an inclusive global forum where professionals from academia, private practice, not-for-profit, government and industry can learn, share and grow to eradicate epilepsy and its consequences.