Epilepsy

Dravet Syndrome: morphologic abnormalities, role of precision medicine, novel mechanisms for treatment and treatment options

Virginia Thornley, M.D., Neurologist, Epileptologist
@VThornleyMD

August 13, 2018


Introduction

Dravet syndrome is characterized by developmental delay and intractable predominantly myoclonic seizures related to an abnormality in the SCN1A gene. The SCN1A gene encodes for sodium channel Nav1.1 which is voltage gated. It is one of the most pharmacologically resistant types of epilepsy syndromes.

Functional and morphological studies

One animal study using SCN1a(E1099x/HET mouse model for Dravet syndrome demonstrated early seizures which reached its maximum at post-natal week 4. There were less GABAergic neurons that expressed the Nav1.1 subunit in the dentate gyrus in the Het mice. There was a reduced number of inhibitory inputs travelling to the dentate gyrus cells in the Het mice. There was an increase in transmissions of excitatory impulses. The dentate gyral cells were noted to be abnormal morphologically with less arborization and a greater number of spines(1). This correlated with the abnormal excitation and reduced inhibition.

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Fenfluramine

Fenfluramine has been revisited as a treatment option for Dravet syndrome. It is metabolized into norfenfluramine. Fenfluramine and its metabolite norfenfluramine uncouples the association of sigma 1 receptor from the NR1 subunit of NMDA receptors (glutamate N-methyl-D-aspartate). Fenfluramine has serotonergic activity at the 5HT2AR receptor in addition to the activity at the sigma 1 receptor which reduces convulsive activity. Fenfluramine influences the cannabinoid type 1 receptor uncoupling with NMDARs which allowed greater restriction of the NMDAR actions (2).

Ketogenic diet

Ketogenic diet should not be discounted as a therapeutic option (3). In a study of 52 patients with pharmacoresistent epilepsy, spike and sharp wave complexes were reduced on the electroencephalograms of 26 patients which was significant (p<0.5). After a treatment of 12 weeks, there was a noticeable effective rate if seizure reduction of 42%. Motor, language and cognition was found to be improved in 23 patients, although the degree of improvement was not thought to be significant. Some adverse reactions included digestive problems and elevated liver enzymes.

Precision medicine

Because Dravet syndrome is related to a de novo loss of function mutation, great interest has been generated towards precision medicine. This involves targeting the genetic abnormality with treatments tailored towards a patient’s particular genetic make-up.

In one study using precision medicine, the selective activation of the Nav1.1 through the venom Hm1a restored the inhibitory mechanism of the neurons that are responsible for causing seizures in the mice model for Dravet syndrome (4). This may be a novel target for a therapeutic option using precision medicine in the treatment of Dravet syndrome.

Summary

In summary, while Dravet syndrome continues to be a devastating neurological disorder, there is research in precision medicine and other novel therapeutic options that can pave the way for more studies in this area.



https://neurologybuzz.com/

Reference

1. Tsai, M.S., Lee, M.L., Chang, C.Y., Fan, H.H., Yu, I.S., You, J.Y., Chen, C.Y., Chang, F.C., Hsiao, J.H., Khorkova, O., Liou, H.H.,Yanagawa, Y., Lee, L.J., Lin, S.W. Functional and structural deficits of the dentate gyrus network coincide with the emerging spontaneous seizures in an Scn1a mutant Dravet syndrome model during development. Neurobiol Dis 2015, May, 77:35-48
2. Rodriguez-Munoz, Maria, Sanchez-Blasquez, Pilar, Garzon, Javier. Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget. 2018, May, 9(34):23373-23389
3. Qiong, W., Hua, W., Yu, Y., Mei Zhang, J., Yan Liu, X., Ying Fang, X., Hua Yang, F., Jun Cao, Q., Qi, Ying. Ketogenic diet effects on 52 children with pharmacoresistent epileptic encephalopathy: a clinical prospective study. Brain Behav. 2018, May, 8(5):e00973
4. Richards, K.L., Milligan C.J., Richardson, R.J., Jancovski, N., Grunnet, M., Jacobson, L.H., Undheim, EAB, Mobli, M., Chow, C.Y., Herzig, V., Csoti, A., Panvi, G., Reid, C.A., King, G.F., Petrou, S. Selective Nav1.1 activation rescues Dravet syndrome mice from seiuzres and premature death. Proc. Natl. Acad. Sci. U.S.A. 2018, Aug. pii:201804764

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Cancer research and cannabinoids

Cannabinoids: potential role in the detection and reduction of pancreatic tumor load in pre-clinical studies

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

August 1, 2018

Introduction

Cannabinoids are gaining more recognition in treatment not only of pain, seizures and mood disorder but also in a wide variety of conditions. There have been 3 decades of pre-clinical research studying the mechanisms as it relates to the different organ systems. There has been an exponential increase in cannabinoid research especially in light of the demand by grassroot movements for it availability in treating a wide variety of conditions.

As more and more physicians start to recommend it, more symptoms are coming to light which can be ameliorated with medical cannabis. One of the most sought after answer is the deadliest of diseases which is cancer. This seeks to study the mechanisms by which cannabinoids may play a role in reduction of tumor load.

Studies

There are many studies demonstrating the involvement of the endocannabinoid system in modulating the pathogenesis of tumors.

There are no published human clinical trials using cannabinoids in the treatment of the actual underlying pancreatic cancer. Cannabis is labelled under the schedule 1 classification, with that comes the difficulty with procuring the agent because of the bureaucracy and legal red tape that accompanies it. Regardless, there has been an exponential increase in pre-clinical studies in in vitro and in vivo studies.

Detection of pancreatic duct cancer using a CB2 probe

A study showed that the CB2 receptor is highly expressed in pancreatic duct cancer which seems to correlate with  the aggressiveness of the tumor (1). One study reports on using fluorescence imaging on pancreatic duct cancer using an NIR (near infrared) CB2 receptor targeted probe (2). The study found a high level of expression of CB2 receptors in patient samples with pancreatic cancer compared to normal pancreatic tissue. This is significant because it gives information on a specific target for diagnostic and treatment purposes.

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Cannabinoid involvement in autophagy through the AMPK pathway

In one study the cannabinoid receptor ligands were discovered to cause autophagy and activate AMPK in pancreatic cancer.  In previous works by the same authors, cannabinoids were found to increase the radical oxygen species. In another study ROS was found to interact with the mitochondria where ATP is produced. AMP is upregulated instead leading to AMPK production which reduces mTOR1c and leads to an increase in autophagy and reduction of cell growth (3).

Possible therapeutic role of CB1 and CB2 receptor ligands on pancreatic cancer

In another study using pancreatic cancer cell lines Panc1, 2 cannabinoid receptor ligands were applied to study the mechanisms of cannabinoids and its possible anti-tumor effect. Cannabinoid ligands GW405833 and arachidonoyl cyclopropramide. The study showed that the cannabinoid ligands were involved in the down-regulation and up-regulation of proteins associated with regulation of cell growth and their energy metabolism. This could be a potential target for therapeutic approaches in pancreatic cancer (4).

Synergistic responses occur when CBD is combined with radiation

Cannabidiol can augment the tumor killing potential when combined with radiation therapy in pancreatic cancer which was studied under in vitro studies. Synergistic responses were noted when 5 micrograms of CBD was combined with 4Gy of radiation therapy in a clonogenic assay. In the same study using mice, there was increased survival in mice with pancreatic tumor using CBD compared to a  control cohort. When CBD was added with SRB or smart biomaterials (agents which are sensitive to environmental factors that allow delivery of other agents in this case CBD to the tumor cells) the mice survived compared to the control cohort with just CBD application alone. This study demonstrates that CBD in conjunction with radiation therapy enhances the tumor killing properties in the treatment of pancreatic cancer (5).

SRB’s or smart radiotherapy biomaterials allow the insertion of payloads which allow the abscopal effects of radiation therapy thereby boosting its results (6). Abscopal refers to the idea that radiation treatment can affect tumors distant from the area treated.

In summary

While there may be a dearth of human clinical trials using cannabinoids for treatment in pancreatic cancer, the pre-clinical studies demonstrate that the endocannabinoid system may play a potential role in the mechanisms, diagnosis and treatment of pancreatic cancer, one of the deadliest tumors, and should not be discounted. More studies are needed especially human clinical trials.

References

1. Carracedo, A., Gironella, M., Lorente, M., Garcia, S., Guzman, M., Velasco, G., Iovanna, J.L. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res. 2006, Jul, 66(13):6748-55
2. Guo, X., Ling, X., Du., F., Wang, Q., Huang, W., Wang, Z., Ding, X., Bai, M., Wu, Z. Molecular imaging of pancreatic duct adenocarcinoma using the type 2 cannabinoid targeted near-infrared fluorescent probe. Transl Oncol. 2018, Jul. 11(5):1065-1073
3. Dando, I., Donadelli, M., Costanzo, C., Dalla Pozza, E., D’Alessandro, A., Zolla, L., Palmieri, M. Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell Death Dis. 2013, Jun 13, 4 e664
4. Brandi, J., Dando, I., Palmieri, M., Donadelli, M., Cecconi, D. Comparative proteomic and phosphosproteomic profiling of pancreatic adenocarcinoma treated with CB1 and CB2 agonists. Electrophoresis. 2013, May, 34(9-10):1359-1368
5. Moreau, M., Yasmin-Karim, S., Kunjachan, S., Sinha, N., Gremse, F., Kumar, R., Fan Chow, K., Ngwa, W. Priming the abscopal effect using multifunctional smart radiotherapy biomaterials loaded with immunoadjuvants, Front Oncol 2018, 8:56
6. Yasmin-Karim, S., Moreau, M., Mueller, R., Sinha, N., Dabney, R., Herman, A., Ngwa, W. Enhancing the therapeutic efficacy of cancer treatment with cannabinoids. Front Oncol 2018 Apr 24 (8):114
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