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Leptin as a new approach for treatment for autism and epilepsy, a hypothesis with clinical implications
Brain & Development 33 (2011) 92–93 www.elsevier.com/locate/braindev
Letter to the Editor Leptin as a new approach for treatment for autism and epilepsy, a hypothesis with clinical implications In a recently published article entitled as: “Autism spectrum disorders and epilepsy: Moving towards a comprehensive approach to treatment”, Tuchman et al., mentioned lack of a treatment protocol for children with ASD or epilepsy. There is no definitive evidence for developing medication managements targeting both ASD and epilepsy [1]. It is not clear whether there is a common cause for the co-occurrence of autism and epilepsy [1]. “Understanding of the pathogenesis common to both ASD and epilepsy will provide an avenue for novel therapeutics” [1]. Herein, I would like to mention some evidence for the possible association of leptin in both epilepsy and autism. Also, according to the evidence, possible clinical and research implication for leptin are suggested. Leptin plays a role in modulating structure and synaptic communication in brain [2,3]. some studies on animal models reported that chronic leptin deficiency in mice raise susceptibility to seizure [4] and leptin administering in rodent seizure models suppresses seizures via direct effects on glutamate neurotransmission [5,6]. So, leptin receptor activation is suggested as a novel targets for treatment of epilepsy in animal [7]. However, another recently published study on animal model indicated dose-related proconvulsant activity of leptin [8]. Leptin resistance and increased blood level of leptin is reported in epilepsy in human [9]. Given that, leptin level in autism is higher than controls [10,11]. Also, long-term plasma leptin levels in Rett syndrome is reported [12]. It is worth conducting studies investigating possible difference between the group of ASD with epilepsy and the group of ASD without epilepsy regarding leptin level and its receptor resistance. Probably, leptin may be a link between autism and epilepsy that provides an avenue for novel or better management of autistic children with epilepsy. For example, Ketogenic diets which are effective for epilepsy management increase leptin level in Young rodents [13]. Does Ketogenic diets or antiepileptic medications that increase leptin level exacerbate autism symptoms?
[2] Moult PR, Harvey J. Hormonal regulation of hippocampal dendritic morphology and synaptic plasticity. Cell Adh Migr 2008;2:269–75. [3] Harvey J. Leptin: a multifaceted hormone in the central nervous system. Mol Neurobiol 2003;28:245–58. [4] Erbayat-Altay E, Yamada KA, Wong M, Thio LL. Increased severity of pentylenetetrazol induced seizures in leptin deficient ob/ ob mice. Neurosci Lett 2008;433:82–6. [5] Diano S, Horvath TL. Anticonvulsant effects of leptin in epilepsy. J Clin Invest 2008;118:26–8. [6] Shanley LJ, O’Malley D, Irving AJ, Ashford ML, Harvey J. Leptin inhibits epileptiform-like activity in rat hippocampal neurones via PI 3-kinase-driven activation of BK channels. J Physiol 2002;545: 933–44. [7] Xu L, Rensing N, Yang XF, Zhang HX, Thio LL, Rothman SM, et al. Leptin inhibits 4-aminopyridine- and pentylenetetrazoleinduced seizures and AMPAR-mediated synaptic transmission in rodents. J Clin Invest 2008;118:272–80. [8] Lynch 3rd JJ, Shek EW, Castagne´ V, Mittelstadt SW. The proconvulsant effects of leptin on glutamate receptor-mediated seizures in mice. Brain Res Bull 2010;82:99–103. [9] Hamed SA. Leptin and insulin homeostasis in epilepsy: relation to weight adverse conditions. Epilepsy Res 2007;75:1–9. [10] Blardi P, de Lalla A, Ceccatelli L, Vansessa G, Auteri A, Hayek J. Variations of plasma leptin and adiponectin levels in autistic patients. Neurosci Lett 2010;479:54–7. [11] Ashwood P, Kwong C, Hansen R, Hertz-Picciotto I, Croen L, Krakowiak P, et al. Brief report: plasma leptin levels are elevated in autism: association with early onset phenotype? J Autism Dev Disord 2008;38:169–75. [12] Blardi P, de Lalla A, D’Ambrogio T, Vonella G, Ceccatelli L, Auteri A, et al. Long-term plasma levels of leptin and adiponectin in Rett syndrome. Clin Endocrinol (Oxf) 2009;70:706–9. [13] Yamada KA. Calorie restriction and glucose regulation. Epilepsia 2008;49:94–6.
Ahmad Ghanizadeh Child and Adolescent Psychiatry, Shiraz University of Medical Sciences, Shiraz, Iran Research Center for Psychiatry and Behavioral Sciences, Hafez Hospital, Shiraz, Iran Tel./fax: +98 711 627 93 19 E-mail addresses: [email protected], [email protected] 0387-7604/$ - see front matter Ó 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2010.08.003
Reply to Dr. Ghanizach References To the Editors: [1] Tuchman R, Alessandri M, Cuccaro M. Autism spectrum disorders and epilepsy: moving towards a comprehensive approach to treatment. Brain Dev 2010;32:719–30.
We appreciate the interest and comments by Dr. Ghanizaeh regarding our article “Autism spectrum dis-
Letter to the Editor Leptin as a new approach for treatment for autism and epilepsy, a hypothesis with clinical implications In a recently published article entitled as: “Autism spectrum disorders and epilepsy: Moving towards a comprehensive approach to treatment”, Tuchman et al., mentioned lack of a treatment protocol for children with ASD or epilepsy. There is no definitive evidence for developing medication managements targeting both ASD and epilepsy [1]. It is not clear whether there is a common cause for the co-occurrence of autism and epilepsy [1]. “Understanding of the pathogenesis common to both ASD and epilepsy will provide an avenue for novel therapeutics” [1]. Herein, I would like to mention some evidence for the possible association of leptin in both epilepsy and autism. Also, according to the evidence, possible clinical and research implication for leptin are suggested. Leptin plays a role in modulating structure and synaptic communication in brain [2,3]. some studies on animal models reported that chronic leptin deficiency in mice raise susceptibility to seizure [4] and leptin administering in rodent seizure models suppresses seizures via direct effects on glutamate neurotransmission [5,6]. So, leptin receptor activation is suggested as a novel targets for treatment of epilepsy in animal [7]. However, another recently published study on animal model indicated dose-related proconvulsant activity of leptin [8]. Leptin resistance and increased blood level of leptin is reported in epilepsy in human [9]. Given that, leptin level in autism is higher than controls [10,11]. Also, long-term plasma leptin levels in Rett syndrome is reported [12]. It is worth conducting studies investigating possible difference between the group of ASD with epilepsy and the group of ASD without epilepsy regarding leptin level and its receptor resistance. Probably, leptin may be a link between autism and epilepsy that provides an avenue for novel or better management of autistic children with epilepsy. For example, Ketogenic diets which are effective for epilepsy management increase leptin level in Young rodents [13]. Does Ketogenic diets or antiepileptic medications that increase leptin level exacerbate autism symptoms?
[2] Moult PR, Harvey J. Hormonal regulation of hippocampal dendritic morphology and synaptic plasticity. Cell Adh Migr 2008;2:269–75. [3] Harvey J. Leptin: a multifaceted hormone in the central nervous system. Mol Neurobiol 2003;28:245–58. [4] Erbayat-Altay E, Yamada KA, Wong M, Thio LL. Increased severity of pentylenetetrazol induced seizures in leptin deficient ob/ ob mice. Neurosci Lett 2008;433:82–6. [5] Diano S, Horvath TL. Anticonvulsant effects of leptin in epilepsy. J Clin Invest 2008;118:26–8. [6] Shanley LJ, O’Malley D, Irving AJ, Ashford ML, Harvey J. Leptin inhibits epileptiform-like activity in rat hippocampal neurones via PI 3-kinase-driven activation of BK channels. J Physiol 2002;545: 933–44. [7] Xu L, Rensing N, Yang XF, Zhang HX, Thio LL, Rothman SM, et al. Leptin inhibits 4-aminopyridine- and pentylenetetrazoleinduced seizures and AMPAR-mediated synaptic transmission in rodents. J Clin Invest 2008;118:272–80. [8] Lynch 3rd JJ, Shek EW, Castagne´ V, Mittelstadt SW. The proconvulsant effects of leptin on glutamate receptor-mediated seizures in mice. Brain Res Bull 2010;82:99–103. [9] Hamed SA. Leptin and insulin homeostasis in epilepsy: relation to weight adverse conditions. Epilepsy Res 2007;75:1–9. [10] Blardi P, de Lalla A, Ceccatelli L, Vansessa G, Auteri A, Hayek J. Variations of plasma leptin and adiponectin levels in autistic patients. Neurosci Lett 2010;479:54–7. [11] Ashwood P, Kwong C, Hansen R, Hertz-Picciotto I, Croen L, Krakowiak P, et al. Brief report: plasma leptin levels are elevated in autism: association with early onset phenotype? J Autism Dev Disord 2008;38:169–75. [12] Blardi P, de Lalla A, D’Ambrogio T, Vonella G, Ceccatelli L, Auteri A, et al. Long-term plasma levels of leptin and adiponectin in Rett syndrome. Clin Endocrinol (Oxf) 2009;70:706–9. [13] Yamada KA. Calorie restriction and glucose regulation. Epilepsia 2008;49:94–6.
Ahmad Ghanizadeh Child and Adolescent Psychiatry, Shiraz University of Medical Sciences, Shiraz, Iran Research Center for Psychiatry and Behavioral Sciences, Hafez Hospital, Shiraz, Iran Tel./fax: +98 711 627 93 19 E-mail addresses: [email protected], [email protected] 0387-7604/$ - see front matter Ó 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2010.08.003
Reply to Dr. Ghanizach References To the Editors: [1] Tuchman R, Alessandri M, Cuccaro M. Autism spectrum disorders and epilepsy: moving towards a comprehensive approach to treatment. Brain Dev 2010;32:719–30.
We appreciate the interest and comments by Dr. Ghanizaeh regarding our article “Autism spectrum dis-