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| Introduction | Neuroscientific Context | Critical Analysis | Appendix | References | Who We Are

Introduction


Our chosen media piece is an article, which talked about a new study that appeared in the June 12, 2013 issue of The Journal of Neuroscience. A new drug, nimodipine, has been identified to significantly reduce the occurrence and duration of febrile seizures in animals. Published on June 11, 2013 on Science Daily, the article examines the function of calcium channels in providing a target for the treatment of febrile seizures.

Febrile seizures are convulsions associated with a sudden rise in body temperature in young kids as opposed to it being prolonged for a period of time (Snider, 1998). They mostly affect children between the ages of six months to six years and occur twice more often in boys than in girls (Snider, 1998). About 3 in 100 children are also known to have a febrile seizure before their sixth birthday.

During a febrile seizure, a child may lose consciousness and shake and twitch their limbs. This will be followed by a brief period of drowsiness for some kids and most of the time, these febrile seizures will stop without treatment.

They occur in young children and infants due to the high frequency of infections to otitis media and upper respiratory tract (Noggle et al., 2012). Young children respond to relatively higher temperatures than adults as a result of fighting against these infections (Hirtz, 1997). Fetveit (2007) has indicated that the main cause for febrile seizures is viral illnesses. A bacterial infection, Shigella gastroenteritis has also been found to be associated with febrile seizures (Hirtz, 1997).

There are two kinds of febrile seizures, simple febrile seizures where convulsions usually last for a short duration with no focal features and complex febrile seizures where convulsions usually last for up to 40 minutes and usually has focal features (Noggle et al., 2012; Shinnar, 2005). Furthermore, simple febrile seizures do not recur within a 24-hour period or within the same illness but complex febrile seizures may recur within a 24-hour period or several times within the same illness (Shinnar, 2005). In addition, simple febrile seizures are reported with approximately 80% to 85% of febrile seizures but complex febrile seizures only account for approximately 15% to 20% (Noggle et al., 2012).

Nonetheless, to date, there is still no exact explanation as to why febrile seizures occur but some scientists have proposed that they are linked to viral or bacterial infections in the child’s body.

The article is of interest because the new drug could potentially lead to advancement in clinical care, and might stop seizures elicited by high temperatures in young children, prevent seizure recurrence as well as minimize the likelihood of any health complications that the seizures might cause in the long term.



Neuroscientific Context


Generation of febrile seizures


The mechanisms that cause the generation of febrile seizures are still poorly understood. However, recently, there have been a few studies associating a mutated GABAA receptor γ2 subunit gene with febrile seizures. All patients with febrile seizures were reported to have this mutated gene, which made scientists conclude that there is a strong relationship between febrile seizures occurrence and impaired GABAA receptor γ2 subunit function (Kang, Shen & Macdonald, 2006).

The γ2 subunit missense and truncation mutations were found to be in different locations. This means that not all mutations are likely to cause a particular functional consequence. Some of the functions of the γ2 subunit include receptor trafficking (Keller et al., 2004), clustering (Essrich et al., 1998) and synaptic maintenance (Schweizer et al., 2003), implying that these mutated receptors have a temperature-dependent effect on surface receptor stability (Kang et al., 2006).

Seizure recurrence


Previous studies have showed that neuropeptide Y (NPY) played a role in reducing the chances of seizure recurrence by increasing the seizure thresholds. In a particular study conducted in 2007, rat models were induced with experimental febrile seizures at three to four hour intervals. The results were an increase in seizure threshold for subsequent seizures and from Figure 1, it can be seen that threshold for the 2nd seizure is higher than the 1st and the 3rd seizure is higher than the 2nd. However, this effect was terminated when an antagonist against NPY receptor type 2 was applied as seen in Figure 2 (Dubé, 2007). This suggests that NPY has an effect on reducing the risk of seizure recurrence by increasing threshold level.


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Figure 1: Increased threshold temperatures for subsequent seizures (Dubé et al., 2005)


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Figure 2: Effect of antagonist on NPY receptor type 2 (Dubé, 2007)


Description of the drug


Nimodipine is isopropyl (2 - methoxyethyl) 1, 4 - dihydro - 2, 6 - dimethyl - 4 - (3 - nitrophenyl) - 3, 5 - pyridine - dicarboxylate. Moreover, it is a racemic mixture with a molecular weight of 418.5 and a molecular formula of C21H26N2O7
The structural formula of Nimodipine is:


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Figure 3: Molecular structure of Nimodipine (Source: Wikimedia)



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Figure 4: NIMOTOP© capsule (Source: cvs)



Nimodipine (NIMOTOP© founded by Bayer) is an insoluble yellow crystalline substance.
NIMOTOP© capsule (Figure 4) is made from soft gelatin capsules that contains gelatin, purified water and titanium dioxide for oral administration. Each capsule contains 30 mg of nimodipine in a vehicle of glycerin, peppermint oil, purified water and polyethylene glycol 400. The drug should be stored at room temperature between 15 and 30 degree Celcius and freezing is not recommended.

Uses of Nimodipine


Nimodipine is a calcium channel blocker which affects the flow of calcium in and out of certain body cells and also relaxes blood vessels (Hochadel et al., 2006). Nimodipine inhibits the transfer of calcium ion into these cells and thus the contractions of vascular smooth muscles are also inhibited. Furthermore, it is used to treat patients with cerebral vasospasm after subarachnoid haemorrhage. It is used to increase blood to the injured brain tissue when haemorrhage occurs (Loughlin et al., 2006). Belfort et al. (2003) also found that nimodipine helps in preventing seizures in women with severe preeclampsia.

Side effects of Nimodipine


Drinks like grapefruit juice may interact with nimodipine hence it is dangerous to consume it with grapefruit juice (Maryanne et al., 2006). Moreover, nimodipine may also interact with the some medications for example, anti-flammatory drugs such as ibuprofens, herbal or dietary supplements such as gingko biloba, ginseng, hawthorn and melatonin, medicines for high blood pressure, medicines for HIV infection, medicines for prostate problems, water pills such as diuretics and more (Maryanne et at., 2006). Side effects typically include dizziness, constipation, hot flashes, nausea, fast or slow heart beat, depression and unusual bruising or bleeding (Loughlin et al., 2006; Maryanne et al., 2006). However, the safety and effectiveness for this drug in children has not been established yet.


Role of L-type calcium channels in febrile seizures


A febrile seizure generally occurs between of the age six months to six years in infants where a rapid rise in temperature occurs. Other possible causes also include respiratory infections in the upper tract and other fever inducing diseases with seizures generally lasting 15 seconds to 15 minutes and over. This is under constant research, where certain anti-convulsion drugs are being tested with some having effectiveness in reducing seizure occurrence with the drawback due to toxicity to patients. Drugs such as carbamazepine and phenytoin being sodium channel blockers are examples of this as toxicity in cells can be achieved readily and therefore more viable drugs are needed to be found to not induce this and being effective in reducing febrile seizure occurrence and duration.

We can clearly discern that it is the unexpected firing by specific channels, which leads to the seizure itself occurring. Through research on mice, it has been shown that there is a link between uncoupled/unexpected firing of L-type calcium channels contributing to temperature-dependent intrinsic firing and therefore being a critical cause in febrile seizures (Radzicki, 2013). Voltage-gated calcium channels are key coupling membranes that allow depolarisation to occur where an influx of extracellular calcium ions move into an excitable cell. Furthermore, calcium dependent channels are important in contraction of muscles and excitation in neurons and endocrine cells. This leads to the generation and movement of electrical/chemical signals.

Recent research where a patch-clamp method of recording values was made where Nimodipine was administered to mice (Radzicki, 2013). Nimodipine being effective on L-type calcium channels such as Cav1.2 calcium channel (Fig. 5) within the hippocampus of rats. These were shown to be temperature sensitive in activity where nimodipine was effective in reducing febrile seizure duration and incidence. Nimodipine is of many other safe and effective L-type calcium channel blockers that are FDA approved and thus completely safe for use by infants/children. This is overwhelming experimental evidence providing new ways for prevention of febrile seizures and a step closer for an effective cure to be established. We can therefore say that an unexpected firing rate (intrinsic) of L-type calcium channels leading to hyperpolarisation is an important cause of febrile seizure and one in which can be induced to a certain extent via introduction of L-type calcium channel blockers such as nimodipine.


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Figure 5: Simplified version of a Cav1.2 calcium channel





Critical Analysis


The article summarises a finding conducted by a team of medical researchers at the Northwestern University Fienberg School of Medicine.

The target audiences are readers interested within the science field, as well as scientists within the research community. The website Science Daily denotes the website as a destination for the latest news in scientific advancements.

The style of writing further emphasizes this point. The level of language used in the article barely does the research any justice, leaving out major points within the paper by summarising important results into one-sentence summaries.

Despite this, it does the job in getting the general results across to non-specialists and provides it in a succinct manner.
In regards to nimodipine itself, a quick check on search engines reveals it to have serious (though rarely fatal) side effects if used incorrectly. Considering the drug would be used primarily for children, it is typical that misuse would occur.

It is also important to keep in mind that nimodipine is a drug that prevents the chance of febrile seizures onset, and it does not cure/alleviate the episodes themselves. Another point to mention is the statement in the article by the associate professor; “…every toddler with febrile seizures can potentially be treated to stop or prevent seizures…”. This is a strong claim, especially since they conducted the research on animal models and no clinical trials have been conducted within the human population yet. As such the associate professor promotes this finding with an over-zealous nature.

Another new method currently being explored in managing febrile seizures is the use of administering carbon dioxide via inhalation actually stopping the febrile seizures itself has emerged. This is another promising field and is being promoted by Ohlraun and colleagues in their recent paper.

Despite the shortcomings of the article, the research in the journal itself provides a new hope for the prevention of febrile seizures beyond simply managing the anxiety that parents feel when their offspring suffer from febrile seizures, however this data is not yet conclusive and only suggests further experimentation using nimodipine. Prior studies have only focused on sodium channels (Thomas et al. 2009; Kang, Shen & Macdonald, 2006), suggesting that sodium itself or calcium itself may not be the complete story in the mechanisms of febrile seizures, thus more causational studies need to be conducted as a future implication in looking at how these two types of channels interact when high temperatures cause seizures in infants.





Appendix


At the start, we were contemplating between three articles, one on Alzheimer’s, another on stress and this one. Our choices mainly came from journals on web sources such as Neuroscience News, Science Daily and Science Magazine. In the end, we picked this article on febrile seizure, as we wanted a topic that we have learnt to be incorporated into our research.

Within the critical analysis, research has been done on the background of febrile seizures, for example, "What current knowledge do we have on sodium channels?", "What current treatments are available regardless of this new research?" and more. Having read the article that the Science Daily is featuring, it becomes apparent that a lot of information about how the experiments are conducted or what methods are used has been left out. Considering that Science Daily is more of a news/media outlet than a reviewing agent, it is understandable that not as much information is accounted in their feature. Database research in the critical analysis included the use of PubMed (ncbi) as well as other databases such as WileyOnline.

Comments from reviewers pointed out our lack of pictures and information for the neuroscientific context section as well as our grammatical and syntax errors. In addition, they also advised us to read the marking criteria as we were missing some points in the introduction. To address all this, we made all the necessary changes and added more pictures and background information to make the page look better and more informative. However, some of these concerns such as more information of the drug were dismissed, as the area of research is very limited, or in the case of opposing opinions, the majority say is taken on board.




References


Belfort. M.A., Anthony. J., Saade, G.R., Allen, J.C. (2003). A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia". N. Engl. J. Med. 348 (4): 304–11.

Dubé, C. (2007) Neuropeptide Y: potential role in recurrent developmental seizures Peptides 28(2), 441-446.

Dubé, C., Brunson, K.L., Eghbal-Ahmadi, M., Gonzalez-Vega, R., Baram, T.Z. (2005). Journal of Molecular Neuroscience 25(3), 275-284.

Essrich, C., Lorez, M., Benson, J.A., Fritschy, J.M., Luscher, B. (1998). Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin. Nat Neurosci 1, 563–571.

Fetveit, A. (2007). Assessment of febrile seizures in children. European Journal of Pediatrics, 167(1), 17-27.

Hirtz, D.G. (1997). Febrile seizures. Pediatric Review, 18(1), 5-8.

Hochadel, M., Avorn, J., Thomas, W.H., Greider, K. (2006). The AARP Guide to Pills: Essential Information on More Than 1,200 Prescription and Nonprescription Medicines, Including Generics. New York, NY: Sterling Publishing Company Inc, 672-673.

Jones. T, Jacobsen S.J. (2007) Childhood febrile seizures: overview and implications. Int J Med Sci.4(2):110-4.

Loughlin, K., Generali, J., Dell, D., Ossias, L., Hulka, F., Silva, O., Hoke, A., Brown, K., Dempsey, M., Parisi, E., Hinthorn, D., Bridges, A., Garbutt. J.C., Jamidar, P., Almajameed, A. (2005).

Kang, J. Q., Shen, W., & Macdonald, R. L. (2006). Why does fever trigger febrile seizures? GABAA receptor γ2 subunit mutations associated with idiopathic generalized epilepsies have temperature-dependent trafficking deficiencies. The Journal of neuroscience, 26(9), 2590-2597.

Kang, J., Shen, W., Macdonald, R. L. (2006). The Journal of Neuroscience 24, 8762-8677.

Keller, C.A., Yuan, X., Panzanelli, P., Martin, M.L., Alldred, M., Sassoe-Pognetto, M., Luscher, B. (2004). The γ2 subunit of GABAA receptors is a substrate for palmitoylation by GODZ. J Neurosci 24, 5881–5891.

Mazarati, A.M. (2005). Cytokines: A link between fever and seizures. Epilepsy Currents, 5(5), 169-170.

Mikati, M.A. Febrile seizures.In: Kliegman RM,Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. Chapter 586.1

Noggle, C.A., Dean, R.S., Horton, A.M. (2012). The Encyclopedia of Neuropsychological Disorders. Springers Publishing Company, LLC, 31

Ohlraun, S. et al. (2013) Carbon dioxide for the treatment of febrile seizures: rationale, feasibility, and design of the CARDIF-study. Journal of Translational Medicine. (11):157

Radzicki, D., Yau, H., Pollema-Mays, S., Misna, L., Cho, K., Koh, S. and Martina, M. (2013). Temperature-sensitive Cav1.2 calcium channels support intrinsic firing of pyramidal neurons and provide a target for the treatment of febrile seizures.Neuroscience, 33 (24), 9920-31.

Schweizer, C., Balsiger, S., Bluethmann, H., Mansuy, I.M., Fritschy, J.M., Mohler, H., Luscher, B. (2003). The gamma 2 subunit of GABAA receptors is required for maintenance of receptors at mature synapses. Mol Cell Neurosci 24, 442–450.

Shinnar, S. (2005). Febrile seizures. In Singer, H.S., Kossoff, E.H., Hartman, A.L., Bryun G.W (Eds.), HAndbook of clinical neurology: The epilepsies part II. Philadelphia, PA: Elsevier Health Sciences, 309-316.

Snider, K. (1998). ATI NurseNotes: Pediatrics (117) Overland Park: Lippincott Raven Publishers.

Thomas, E.A., Hawkins, R. J., Richards, K. L., Xu, R., Gazina, E. V., & Petrou, S. (2009). Heat opens axon initial segment sodium channels: A febrile seizure mechanism?. Annals of neurology, 66(2), 219-226.

William Andrew Publishing (2006). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition, Elsevier, 2935.



Who We Are

Name
Student ID
Jeslyn Phoen
z3430072
Huixin Chiew
z3372288
Hussein Yahfoufi
z3422484
Michael Zhang
z3373659

Work Allocation

Jeslyn- Intro/Generation and recurrence of seizures/Appendix
Huixin- Intro/Drug description
Hussein- Role of calcium channels
Michael- Analysis/Appendix

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