REVIEW ARTICLE published: 31 July 2013 doi: 10.3389/fncel.2013.00115 Role of hormones and neurosteroids in epileptogenesis Doodipala Samba Reddy* Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA Edited by: This article describes the emerging evidence of hormonal influence on epileptogenesis, Roberto Di Maio, University of which is a process whereby a brain becomes progressively epileptic due to an initial Pittsburgh, USA precipitating event of diverse origin such as brain injury, stroke, infection, or prolonged Reviewed by: seizures. The molecular mechanisms underlying the development of epilepsy are poorly Corette J. Wierenga, Utrecht University, Netherlands understood. Neuroinflammation and neurodegeneration appear to trigger epileptogenesis. Jafri Malin Abdullah, Universiti Sains There is an intense search for drugs that truly prevent the development of epilepsy in Malaysia, Malaysia people at risk. Hormones play an important role in children and adults with epilepsy. *Correspondence: Corticosteroids, progesterone, estrogens, and neurosteroids have been shown to affect D. Samba Reddy, Department of seizure activity in animal models and in clinical studies. However, the impact of hormones Neuroscience and Experimental Therapeutics, College of Medicine, on epileptogenesis has not been investigated widely. There is emerging new evidence Texas A&M University Health Science that progesterone, neurosteroids, and endogenous hormones may play a role in regulating Center, 8447 State Highway 47, the epileptogenesis. Corticosterone has excitatory effects and triggers epileptogenesis MREB Building, Bryan, TX 77807, USA in animal models. Progesterone has disease-modifying activity in epileptogenic models. e-mail: [email protected] The antiepileptogenic effect of progesterone has been attributed to its conversion to neurosteroids, which binds to GABA-A receptors and enhances phasic and tonic inhibition in the brain. Neurosteroids are robust anticonvulsants. There is pilot evidence that neurosteroids may have antiepileptogenic properties. Future studies may generate new insight on the disease-modifying potential of hormonal agents and neurosteroids in epileptogenesis. Keywords: epilepsy, epileptogenesis, neurosteroid, estrogen, progesterone, kindling INTRODUCTION seizure, therefore, does not constitute epilepsy. The diagnosis Epilepsy, one of the most common serious neurological disorders, of epilepsy requires the occurrence of recurrent (two or more) is characterized by the unpredictable occurrence of seizures. A epileptic seizures separated by at least 24 h, unprovoked by any seizure is an abnormal electrical discharge in the brain that causes immediate identified cause. Antiepileptic drugs (AEDs) are the an alteration in consciousness, sensations, and behaviors. The mainstay for controlling seizures (Table 1). Current drug ther- symptoms that occur depend on the parts of the brain affected apy is symptomatic in that available drugs inhibit seizures, but during the seizure. Common signs of seizures include staring, neither effective prophylaxis nor cure are available. The goal of unusual feelings, twitching, unconsciousness, and jerking in the the therapy is to eliminate seizures without interfering with nor- arms or legs. Epilepsy affects an estimated 3 million Americans mal function (Glauser et al., 2006, 2013). Despite many advances and about 65 million people worldwide in a variety of ways (Jacobs in epilepsy research, presently an estimated 30% of people with et al., 2009; Hesdorffer et al., 2013). About 150,000 new cases of epilepsy have “intractable seizures” that do not respond to even epilepsy are diagnosed in the United States annually (Hesdorffer the best available medication. There is renewed focus on the et al., 2013). Children and adults are the fastest−growing segments pathophysiology of epileptogenesis, the process whereby a brain of the population with new cases of epilepsy. becomes progressively epileptic due to an initial precipitating Epilepsy is a collective designation for a group of brain dis- event. orders consisting of a complex spectrum of different seizure This article describes the emerging evidence of hormonal types and syndromes. Epileptic seizures are classified into par- influence on epileptogenesis and the potential mechanisms under- tial (simple and complex partial seizures) and generalized seizures lying their actions on neuronal excitability and seizure activity. (absence, tonic–clonic, myoclonic, and atonic seizures). Accu- It also describes recent studies on neurosteroid agents that pre- rate diagnosis of seizure type and epileptic syndrome is critical vent or delay the development of epilepsy. The main focus for determining appropriate drug therapy and prognosis. The of the review is on steroid hormones and neurosteroids with International League Against Epilepsy (ILAE) provided a defi- seizure-modulating activity. Neuropeptides and other hormones nition of “seizure” and “epilepsy” (Fisher et al., 2005). A seizure such as oxytocin, neuropeptide-Y, and galanin, which may affect is defined as “a transient occurrence of signs and/or symptoms neuronal excitability, are not discussed here because such descrip- due to abnormal synchronous neuronal activity in the brain.” tion is beyond the scope of this article. The seizure-modulating Epilepsy is defined as “a disorder of the brain characterized by an effects of neuropeptides are discussed elsewhere (Robertson et al., enduring predisposition to generate epileptic seizures.” A single 2011). Frontiers in Cellular Neuroscience www.frontiersin.org July 2013 | Volume 7 | Article 115 | 1 “fncel-07-00115” — 2013/7/29 — 20:17 — page1—#1 Reddy Role of neurosteroids in epileptogenesis Table 1 | List of current antiepileptic drugs. Standard (first generation) Newer (second generation) Carbamazepine (Tegretol) Acetazolamide (Diamox) Clonazepam (Klonopin) Clobazam (Onfi) Chlorazepate (Tranxene) Ezogabine (Potiga) Diazepam (Valium) Felbamate (Felbatol) Divalproex sodium (Depakote) Fosphenytoin (Cerebyx) Ethosuximide (Zarontin) Lacosamide (Vimpat) Ethotoin (Peganone) Lamotrigine (Lamictal) Lorazepam (Ativan) Levetiracetam (Keppra) Mephobarbital (Mebaral) Oxcarbazepine (Trileptal) Methsuximide (Celontin) Parampanel (Fycompa) Nitrazepam (Mogadon) Pregabalin (Lyrica) Phenobarbital (Gardinal) Progabide (Gabrene) Phenytoin (Dilantin) Rufinamide (Banzel) Primidone (Mysoline) Tiagabine (Gabitril) Valproic acid (Depakene) Topiramate (Topamax) Vigabatrin (Sabril) FIGURE 1 | Pathophysiology of epileptogenesis. Epileptogenesis is the process whereby a normal brain becomes progressively epileptic because Zonisamide (Zonegran) of precipitating injury or risk factors such as TBI, stroke, brain infections, or prolonged seizures. Epilepsy development can be described in three stages: (1) the initial injury (epileptogenic event); (2) the latent period (silent period with no seizure activity); and (3) chronic period with spontaneous OVERVIEW OF EPILEPTOGENESIS AND INTERVENTION recurrent seizures. Although the precise mechanisms underlying spatial and temporal events remain unclear, epileptogenesis may involve an STRATEGIES interaction of acute and delayed anatomic, molecular, and physiological Epilepsy is a chronic condition with many possible causes. Epilepsy events that are both complex and multifaceted. The initial precipitating may develop because of an abnormality in neural connectivity, factor activates diverse signaling events, such as inflammation, oxidation, apoptosis, neurogenesis, and synaptic plasticity, which eventually lead to an imbalance in inhibitory and excitatory neurotransmitters, or structural and functional changes in neurons. These changes are eventually some combination of these factors. Primary epilepsy (50%) is idio- manifested as abnormal hyperexcitability and spontaneous seizures. pathic (“unknown cause”). In secondary epilepsy (50%), seizures may result from a variety of conditions including trauma, anoxia, metabolic imbalances, tumors, encephalitis, drug withdrawal, and chemical warfare nerve agents, such as soman, can cause epilepsy neurotoxicity (Engel et al., 2007). The molecular mechanisms as a result of cholinergic neurotoxicity and status epilepticus (de underlying the development of acquired epilepsy are not very Araujo Furtado et al., 2012). well understood. The term “epileptogenesis” is used to describe The development of epileptogenesis is thought to be a step- the complex plastic changes in the brain that, following a precip- function of time after the brain injury, with a latent period itating event, convert a normal brain into a brain debilitated by present between the brain injury and the first unprovoked seizure. recurrent seizures (Pitkänen et al., 2009; Pitkänen and Lukasiuk, There are some alternative hypotheses to this notion that view 2011). Although specific types of epilepsy may have unique patho- epileptogenesis as a continuous process that extends past the physiological mechanisms, a broad hypothesis in this field is that first spontaneous seizure (Dudek and Staley, 2011). Temporal convergent neuronal mechanisms are common in different forms lobe epilepsy (TLE) is one of the common forms of chronic of acquired epilepsy. epilepsies (Wieser and ILAE Commission on Neurosurgery of The current hypothesis about the pathogenesis of epilepsy Epilepsy, 2004). TLE is characterized by the progressive expan- (epileptogenesis) involves three stages: (1) the