Endogenous Levels of Gamma Amino-Butyric Acid Are Correlated to Glutamic-Acid Decarboxylase Antibody Levels in Type 1 Diabetes

Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system (CNS) and outside of the CNS, found in the highest concentrations in immune cells and pancreatic beta-cells. GABA is gaining increasing interest in diabetes research due to its immune-modulatory and beta-cell stimulatory effects and is a highly interesting drug candidate for the treatment of type 1 diabetes (T1D). GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD), one of the targets for autoantibodies linked to T1D. Using mass spectrometry, we have quantified the endogenous circulating levels of GABA in patients with new-onset and long-standing T1D and found that the levels are unaltered when compared to healthy controls, i.e., T1D patients do not have a deficit of systemic GABA levels. In T1D, GABA levels were negatively correlated with IL-1 beta, IL-12, and IL-15 15 and positively correlated to levels of IL-36 beta and IL-37. Interestingly, GABA levels were also correlated to the levels of GAD-autoantibodies. The unaltered levels of GABA in T1D patients suggest that the GABA secretion from beta-cells only has a minor impact on the circulating systemic levels. However, the local levels of GABA could be altered within pancreatic islets in the presence of GAD-autoantibodies.

Stiff-person syndrome with sensorimotor polyneuropathy – case report

Stiff-person syndrome (SPS) is a rare disorder with an estimated prevalence in the general population of 1–2 cases/1,000,000. It is 2–3 times more common in females, with symptom onset at the age of 20–50 years in most cases. Although stiff-person syndrome is associated with antibodies against glutamic acid decarboxylase and amphiphysin, their presence is not necessary for the diagnosis. The treatment should be multidirectional and include immunomodulation, symptomatic treatment as well as monitoring and treatment of overlapping autoimmune, and surgery. We present a case report of a patient diagnosed with stiff-person syndrome overlapping with axonal and demyelinating sensorimotor polyneuropathy. The diagnostic workup indicated diabetes-related polyneuropathy. About 30% of patients diagnosed with stiff-person syndrome also have diabetes. Polyneuropathy alone is rarely reported to overlap with the disorder. In our opinion, polyneuropathy may have a beneficial effect on the clinical presentation of stiff-person syndrome.

Ferulic Acid Inhibits Catamenial Epilepsy Through Modulation of Female Hormones

Approximately 40% of women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. These seizures result from cyclic changes in circulating progesterone and estradiol levels and there is no effective treatment for this form of intractable epilepsy. We artificially increased progesterone levels and neurosteroid levels (pseudo-pregnancy) in adult Swiss albino female mice (19-23 g) by injecting them with pregnant mares' serum gonadotropin (5 IU s.c.), followed by human chorionic gonadotropin (5 IU s.c.) after 46 hours. After this, ferulic acid (25, 50, 100 mg/kg i.p.) treatment was observed for 10 days. During treatment, progesterone, estradiol, and corticosterone levels were estimated in blood on days 1, 5, and 10. Neurosteroid withdrawal was induced by finasteride (50 mg/kg, i.p.), a 5 α-reductase inhibitor on treatment day 9. Twenty-four hours after finasteride administration (day 10 of treatment), seizure susceptibility was evaluated with the sub-convulsant pentylenetetrazol (PTZ) dose (40 mg/kg i.p.). Four to six hours after PTZ, animals were assessed for depression like phenotypes using tail-suspension test (TST). Four to six hours following TST, animals were euthanized, and discrete brain parts (cortex and hippocampus) were separated for estimation of norepinephrine, serotonin, and dopamine as well as glutamic acid decarboxylase enzyme activity. PMSG and HCG treatment elevated progesterone and estradiol levels, assessed on days 1, 5, and 10 causing a state of pseudo-pregnancy. Treatment with finasteride increases seizure susceptibility and depression-like characteristics possibly due to decreased progesterone levels and elevated estrogen levels coupled with decreased monoamine and elevated corticosterone levels. Ferulic acid treatment, on the other hand, significantly decreased seizure susceptibility and depression like behaviours, possibly as a result of increased progesterone, restored estradiol, corticosterone, monoamine, and glutamic acid decarboxylase enzyme activity. We concluded that ferulic acid exhibited antiepileptic effects in a mouse model of catamenial epilepsy and comorbid depression due to its restorative effects on circulating hormones and cerebral monoamine and glutamic acid decarboxylase enzyme activity.