minocycline and Epilepsy

Minocycline, a second-generation tetracycline antibiotic is being widely tested in animals as well as clinical settings for the management of multiple neurological disorders. The drug has shown to exert protective action in a multitude of neurological disorders including spinal-cord injury, stroke, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Being highly lipophilic, minocycline easily penetrates the blood brain barrier and is claimed to have excellent oral absorption (~100% bioavailability). Minocycline possesses anti-inflammatory, immunomodulatory, and anti-apoptotic properties, thereby supporting its use in treating neurological disorders. The article henceforth reviews all the recent advances in the transformation of this antibiotic into a potential antiepileptic/antiepileptogenic agent. The article also gives an account of all the clinical trials undertaken till now validating the antiepileptic potential of minocycline. Based on the reported studies, minocycline seems to be an important molecule for treating epilepsy. However, the practical therapeutic implementations of this molecule require extensive mechanism-based in-vitro (cell culture) and in-vivo (animal models) studies followed by its testing in randomized, placebo controlled and double-blind clinical trials in large population as well as in different form of epilepsies.

Topics: Animals; Anti-Bacterial Agents; Anticonvulsants; Drug Repositioning; Epilepsy; Humans; Minocycline; Nervous System Diseases; Neuroprotective Agents

Epilepsy is one of the most common neurological disorders, with individuals having an increased susceptibility of seizures in the first few years of life, making children at risk of developing a multitude of cognitive and behavioral comorbidities throughout development. The present study examined the role of PI3K/Akt/mTOR pathway activity and neuroinflammatory signaling in the development of autistic-like behavior following seizures in the neonatal period. Male and female C57BL/6J mice were administered 3 flurothyl seizures on postnatal (PD) 10, followed by administration of minocycline, the mTOR inhibitor rapamycin, or a combined treatment of both therapeutics. On PD12, isolation-induced ultrasonic vocalizations (USVs) of mice were examined to determine the impact of seizures and treatment on communicative behaviors, a component of the autistic-like phenotype. Seizures on PD10 increased the quantity of USVs in female mice and reduced the amount of complex call types emitted in males compared to controls. Inhibition of mTOR with rapamycin significantly reduced the quantity and duration of USVs in both sexes. Changes in USVs were associated with increases in mTOR and astrocyte levels in male mice, however, three PD10 seizures did not result in enhanced proinflammatory cytokine expression in either sex. Beyond inhibition of mTOR activity by rapamycin, both therapeutics did not demonstrate beneficial effects. These findings emphasize the importance of differences that may exist across preclinical seizure models, as three flurothyl seizures did not induce as drastic of changes in mTOR activity or inflammation as observed in other rodent models.

Topics: Animals; Convulsants; Disease Models, Animal; Epilepsy; Female; Flurothyl; Immunologic Factors; Male; Mice; Mice, Inbred C57BL; Minocycline; MTOR Inhibitors; Seizures; Sex Factors; Sirolimus; Vocalization, Animal

Epileptogenesis-associated brain inflammation might be a promising target to prevent or attenuate epileptogenesis. Positron emission tomography (PET) imaging targeting the translocator protein (TSPO) was applied here to quantify effects of different dosing regimens of the anti-inflammatory drug minocycline during the latent phase in two rodent models of epileptogenesis. After induction of epileptogenesis by status epilepticus (SE), rats were treated with minocycline for 7 days (25 or 50 mg/kg) and mice for 5 or 10 days (50 or 100 mg/kg). All animals were subjected to scans at 1 and 2 weeks post-SE. Radiotracer distribution was analyzed and statistical parametric mapping (SPM) was performed, as well as histological analysis of astroglial activation and neuronal cell loss. Atlas-based analysis of [

Topics: Animals; Anti-Inflammatory Agents; Brain; Carrier Proteins; Disease Models, Animal; Epilepsy; Female; Male; Mice; Minocycline; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Treatment Outcome

Epilepsy is one of the major neurological disorders frequently associated with psychiatric disorders such as depression. Alteration of tryptophan metabolism towards kynurenine pathway may be one of the plausible reasons for association of depression in epilepsy. Hence, this study was envisaged to evaluate the dose dependent inhibition of indoleamine 2,3-dioxygenase (IDO) enzyme (responsible for shifting tryptophan metabolism) employing minocycline with valproic acid for comprehensive management of epilepsy and comorbid depression. Kindling was induced in male swiss albino mice by administration of pentylenetetrazole subconvulsive dose (35mg/kg, i.p.) at an interval of 48±2h. Kindled animals were treated with saline, valproate (300mg/kg/day i.p.), valproate in combination with different doses of minocycline (10mg/kg; 20mg/kg; 40mg/kg)/day i.p. and minocycline per se (40mg/kg/day i.p.) for 15 days. Except naïve, all the groups were challenged with pentylenetetrazole (35mg/kg i.p.) on day 5, 10, and 15 to evaluate the seizure severity score. Depression was evaluated in all experimental groups using tail suspension and forced swim test on days 1, 5, 10 and 15, 2h after pentylenetetrazole challenge. Results suggested that saline treated kindled animals were significantly associated with depression. Chronic valproate treatment significantly reduced seizure severity score but unable to ameliorate the associated depression. Minocycline supplementation with valproic acid dose dependently ameliorated depression associated with epilepsy. Neurochemical and biochemical findings also supported the behavioural findings of the study. Thus, our results suggested that supplementation of IDO enzyme inhibitors with valproic acid could be explored further for comprehensive management of epilepsy and associated depression.

Topics: Animals; Comorbidity; Corticosterone; Depression; Drug Interactions; Enzyme Inhibitors; Epilepsy; Hippocampus; Indoleamine-Pyrrole 2,3,-Dioxygenase; Male; Mice; Minocycline; Neurotransmitter Agents; Nitrites; Time Factors; Valproic Acid

Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by tumor formation in multiple organs and severe neurologic manifestations, including epilepsy, intellectual disability, and autism. Abnormalities of both neurons and astrocytes have been implicated in contributing to the neurologic phenotype of TSC, but the role of microglia in TSC has not been investigated. The objectives of this study were to characterize microglial activation in a mouse model of TSC, involving conditional inactivation of the Tsc1 gene predominantly in glial cells (Tsc1(GFAP) CKO mice), and to test the hypothesis that microglial activation contributes to epileptogenesis in this mouse model.. Microglial and astrocyte activation was examined in Tsc1(GFAP) CKO mice by ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein immunohistochemistry. Cytokine and chemokine expression was evaluated with quantitative polymerase chain reaction. Seizures were monitored by video-electroencephalography (EEG). The effect of minocycline in inhibiting microglial and astrocyte activation, cytokine expression, and seizures was tested.. Microglial cell number and size were increased in cortex and hippocampus of 3- to 4-week-old Tsc1(GFAP) CKO mice, which correlated with the onset of seizures. Minocycline treatment prevented the increase in number and cell size of microglia in 4-week-old Tsc1(GFAP) CKO mice. However, minocycline treatment had no effect on astrocyte proliferation and cytokine/chemokine expression and the progression of seizures in Tsc1(GFAP) CKO mice.. Microglia cell number and size are abnormal in Tsc1(GFAP) CKO mice, and minocycline treatment inhibits this microglia activation, but does not suppress seizures. Microglia may play a role in the neurologic manifestations of TSC, but additional studies are needed in other models and human studies to determine whether microglia are critical for epileptogenesis in TSC.

Topics: Animals; Astrocytes; Brain; Calcium-Binding Proteins; Cytokines; Disease Models, Animal; Electroencephalography; Epilepsy; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Microglia; Minocycline; RNA, Messenger; Time Factors; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins; Video Recording

Infectious encephalitides are most often associated with acute seizures during the infection period and are risk factors for the development of epilepsy at later times. Mechanisms of viral encephalitis-induced epileptogenesis are poorly understood. Here, we evaluated the contribution of viral encephalitis-associated inflammation to ictogenesis and epileptogenesis using a rapid kindling protocol in rats. In addition, we examined whether minocycline can improve outcomes of viral-like brain inflammation.. To produce viral-like inflammation, polyinosinic-polycytidylic acid (PIC), a toll-like receptor 3 (TLR3) agonist, was applied to microglial/macrophage cell cultures and to the hippocampus of postnatal day 13 (P13) and postnatal day 74 (P74) rats. Cell cultures permit the examination of the inflammation induced by PIC, while the in vivo setting better suits the analysis of cytokine production and the effects of inflammation on epileptogenesis. Minocycline (50 mg/kg) was injected intraperitoneally for 3 consecutive days prior to the kindling procedure to evaluate its effects on inflammation and epileptogenesis.. PIC injection facilitated kindling epileptogenesis, which was evident as an increase in the number of full limbic seizures at both ages. Furthermore, in P14 rats, we observed a faster seizure onset and prolonged retention of the kindling state. PIC administration also led to an increase in interleukin 1β (IL-1β) levels in the hippocampus in P14 and P75 rats. Treatment with minocycline reversed neither the pro-epileptogenic effects of PIC nor the increase of IL-1β in the hippocampus in both P14 and P75 rats.. Hippocampal injection of PIC facilitates rapid kindling epileptogenesis at both P14 and P75, suggesting that viral-induced inflammation increases epileptogenesis irrespective of brain maturation. Minocycline, however, was unable to reverse the increase of epileptogenesis, which might be linked to its absence of effect on hippocampal IL-1β levels at both ages.

Topics: Age Factors; Animals; Animals, Newborn; Anticonvulsants; Antiviral Agents; Brain; Cells, Cultured; Cytokines; Encephalitis; Encephalitis, Viral; Epilepsy; Gene Expression Regulation; Hippocampus; Kindling, Neurologic; Macrophages; Male; Microglia; Minocycline; Poly I-C; Rats; Rats, Wistar; RNA, Messenger; Statistics, Nonparametric

Minocycline, a tetracycline family antibiotic, is known to inhibit microglial activation and proinflammatory cytokine release in animal models. Experimental data show that these immune processes may play a role in epilepto- and ictogenesis. We present the case of a patient with marked reduction in seizure frequency during minocycline therapy with severe symptomatic epilepsy due to an astrocytoma.

Topics: Anticonvulsants; Astrocytoma; Brain Neoplasms; Epilepsy; Humans; Male; Melanoma; Middle Aged; Minocycline; Neoplasms, Multiple Primary; Skin Neoplasms

Epileptogenesis is defined as the process of developing epilepsy - a disorder characterized by recurrent seizures - following an initial insult. Neuronal death, aberrant synaptic plasticity and neuroinflammation play essential roles in epileptogenesis. An effective neuroprotective therapeutic agent should counteract one or, ideally, all the above-mentioned mechanisms. However, antiepileptic drugs obtainable nowadays can only suppress seizures, without antiepileptogenic effects. Matrix metalloproteinase-9 (MMP-9) is a member of matrix metalloproteinase (MMP) family that remodels the extracellular matrix. Recently, cumulative evidence indicates that MMP-9, a key participant in neuronal death, aberrant synaptic plasticity and neuroinflammation, is upregulated in experimental epilepsy models. Increased MMP-9 is also implicated in clinical epilepsy studies. Thus, we hypothesize that MMP-9 may be a novel therapeutic target for epilepsy and some agents, such as S24994, atorvastatin and minocycline, may be potential antiepileptogenic drugs.

Topics: Animals; Anti-Bacterial Agents; Atorvastatin; Epilepsy; Gene Expression Regulation, Enzymologic; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Matrix Metalloproteinase 9; Mice; Minocycline; Models, Biological; Neurons; Pyrroles; Rats; Seizures; Treatment Outcome

Epileptic seizures cause pathological changes such as sclerosis and pyramidal neuronal loss in the hippocampus. Experimentally, epilepsy can be induced by application of various chemicals directly to the cerebral cortex. In this study, epilepsy was induced in rats by intracortical application of 500 IU penicillin G, and the effect of minocycline and doxycycline on the resulting motor incoordination (rotarod) and hippocampal neuronal loss in CA1, CA2 and CA3 fields (optical fractionator method) were investigated. The rotarod performance was reduced in the epilepsy group to 285.1+/-6.9 s (P<0.05 vs. sham-300 s). Minocycline and doxycycline increased this performance to 297.4+/-1.0 s and 296.9+/-1.2 s respectively. No significant difference was detected between minocycline and doxycycline. The present results also showed that the number of neurons (x10(3)) in the sham group was 150+/-9. In the penicillin-epileptic rats, the number was decreased to 105+/-7 (P<0.01). Minocycline, but not doxycycline (125+/-8), significantly increased the number to 131+/-3 (P<0.05). In conclusion, the second generation tetracycline minocycline decreased the loss of hippocampal neurons and motor incoordination in penicillin-epileptic rats. Minocycline could protect against a variety of neurological insults including epilepsy.

Topics: Animals; Ataxia; Cell Count; Doxycycline; Epilepsy; Hippocampus; Male; Minocycline; Neurons; Neuroprotective Agents; Penicillin G; Rats; Rotarod Performance Test