Epilepsy drug therapies to be improved by new targeted approach

New research from the University of Liverpool, in collaboration with the Mario Negri Institute in Milan, published today in the Journal of Clinical Investigation, has identified a protein that could help patients with epilepsy respond more positively to drug therapies.

Epilepsy continues to be a serious health problem and is the most common serious neurological disease. Despite 30 years of drug development, approximately 30% of people with epilepsy do not become free of fits (also called seizures) with currently available drugs.

New, more effective drugs are therefore required for these individuals. We do not fully understand why some people develop seizures, why some go onto develop epilepsy (continuing seizures), and most importantly, why some patients cannot be controlled with current drugs.

Inflammation

There is now increasing body of evidence suggesting that local inflammation in the brain may be important in preventing control of seizures. Inflammation refers to the process by which the body reacts to insults such as having a fit. In most cases, the inflammation settles down, but in a small number of patients, the inflammation continues.

The aim of the research, undertaken by Dr Lauren Walker while she was a Medical Research Council (MRC) Clinical Training Fellow, was to address the important question of how can inflammation be detected by using blood samples, and whether this may provide us with new ways of treating patients in the future to reduce the inflammation and therefore improve seizure control.

The research focused on a protein called high mobility group box-1 (HMGB1), which exists in different forms in tissues and bloodstream (called isoforms), as it can provide a marker to gauge the level of inflammation present.

Predicting drug response

The results showed that there was a persistent increase in these isoforms in patients with newly-diagnosed epilepsy who had continuing seizure activity, despite anti-epileptic drug therapy, but not in those where the fits were controlled.

An accompanying drug study also found that HMGB1 isoforms may predict how an epilepsy patient’s seizures will respond to anti-inflammatory drugs.

Dr Lauren Walker, said: “Our data suggest that HMGB1 isoforms represent potential new drug targets, which could also identify which patients will respond to anti-inflammatory therapies. This will require evaluation in larger-scale prospective trials.”

Innovative scheme

Professor Sir Munir Pirmohamed, Director of the MRC Centre for Drug Safety Science and Programme lead for the MRC Clinical Pharmacology scheme, said: “The MRC Clinical Pharmacology scheme is a highly successful scheme to train “high flyers” who are likely to become future leaders in academia and industry.

“Dr Walker’s research is testament to this and shows how this innovative scheme, which was jointly funded by the MRC and Industry, can tackle areas of unmet clinical need, and identify new ways of treating patients with epilepsy using a personalised medicine approach”.

Researchers show the transmission of the genetic disorder HD in normal animals

Mice transplanted with cells grown from a patient suffering from Huntington’s disease (HD) develop the clinical features and brain pathology of that patient, suggests a study published in the latest issue of Acta Neuropathologica by CHA University in Korea, in collaboration with researchers at Université Laval in Québec City, Canada.

“Our findings shed a completely new light onto our current understanding of how HD begins and develops. We believe that they will also lead to the development of a whole new range of therapies for neurodegenerative diseases of the central nervous system”, explains corresponding author of the study Jihwan Song, professor and director of Neural Regeneration and Therapy Group at the CHA Stem Cell Institute of CHA University.

The researchers have now provided further evidence for this new theory by showing that the abnormal protein coded for this genetic disorder can be transmitted to normal animals by the injection of diseased cells into their brain. “This is the first demonstration that cells carrying a genetic disease are capable of spreading into the normal mammalian brain and lead to the manifestation of behavioral abnormalities associated with the disease”, says Francesca Cicchetti, professor at the Université Laval Faculty of Medecine and researcher at Centre de recherche du CHU de Québec-Université Laval.

HD is an inherited chronic degenerative disorder of the brain characterized by major thinking and motor problems as well as psychiatric disturbances. There is no cure for HD and current treatments are of very limited efficacy. It is caused by a single gene abnormality which leads to the production of a mutant form of a protein called huntingtin (mHtt). The production of this protein in a nerve cell eventually kills it but it has long been thought that this protein cannot spread out of the cell and infect and kill neighbouring ones.

However, in recent post mortem analyses of HD patients who received transplants of non-HD tissue in an attempt to repair their brain, the researchers showed that the mHtt can be found in the graft itself. This suggests that the patient with HD transmitted the mHtt from their brain into the transplant.

Hunting for the brain’s opioid addiction switch

New research by Steven Laviolette’s research team at Western University is contributing to a better understanding of the ways opiate-class drugs modify brain circuits to drive the addiction cycle. Using rodent models of opiate addiction, Dr. Laviolette’s research has shown that opiates affect pathways of associative memory formation in multiple ways, both at the level of anatomy (connections between neurons) and at the molecular levels (how molecules inside the brain affect these connections). The identification of these opiate-induced changes offers the best hope for developing more effective pharmacological targets and therapies to prevent or reverse the effect of opiate exposure and addiction. These results were presented at the 10th Annual Canadian Neuroscience Meeting, that took place  in Toronto, Canada.

“Developing more effective opiate addiction treatments will require a change in the way we view the effects of opiates on the brain. Instead of addiction being a chronic, permanent disease, recent evidence is showing that addiction is controlled by molecular switching mechanisms in the brain, that can be turned on or off with the right interventions” says Dr. Steven Laviolette.

Addiction to opiates is spreading and increasing exponentially, and is currently estimated to affect 15.5 million people worldwide. Opiate drugs’ addictive properties are largely due to the ability of this class of drugs to produce powerful memories associated with the intense experience of pleasure and euphoria they cause. Environmental reminders triggering the recall of these memories can cause a relapse, and these memories can be considered the primary driver of the addiction cycle, from chronic use, to withdrawal and then memory-triggered relapse. For decades, clinical and pre-clinical research considered that opiate consumption caused permanent changes in the brain’s reward circuits, resulting in a persistent vulnerability to relapse. However, more recent investigations have shown that opiates induce changes in multiple brain circuits, including reward and memory circuits, and that these changes are not static, but rather that many drug-induced adaptations could be reversed.

“A critical challenge for addiction research is identifying the precise molecular brain changes caused by addictive drugs like heroin or prescription narcotics”, says Dr. Laviolette. “Once we understand this process, we can develop more effective pharmacological interventions to prevent or reverse them”

Among the targets identified by Dr. Laviolette are receptors and other proteins involved in signalling of a neurotransmitter called dopamine. More specifically, his work has shown that dopamine signalling in two connected brain regions involved in opiate-related memory processing, called the Basolateral Amygdala (BLA), a region deep within the brain, and the medial prefrontal cortex (mPFC), located near the surface of the brain, is switched by opiate exposure. His research shows that in animals that are opiate naïve, never previously exposed to opiates, the reward memory associated with opiates requires a dopamine receptor called D1R in the BLA, and a signalling molecule called extracellular signal-related kinase 1/2 (ERK1/2). Following chronic opiate exposure, however, opiate reward memory formation becomes independent of D1R, and rather depends on a second dopamine receptor, called D2r, and a protein called CaMKII. As CaMKII expression has been associated with consolidation and permanence of memories in other brain regions, this switch may reflect the formation of a stronger and more stable opiate reward memory.

Interestingly, when Dr. Laviolette’s team looked at dopamine signaling inside another brain region also involved in opiate related memory procession, and located closer to the surface of the brain, the mPFC, they found that this signaling was also switched by opiate exposure, but opposite to what was observed in the BLA. In the mPFC, opiate naïve signaling requires CaMKII, while it did not in opiate habituated animals.

Taken together, these results highlight the precise changes and adaptations that occur in the brain following opiate exposure and development of addiction. New pharmacological approaches to target these changes will provide much needed and more effective treatments to reduce the power of drug-related associative memories that drive opiate addiction.