Cannabidiol modulates contextual fear memory consolidation in animals with experimentally induced type-1 diabetes mellitus Yane Costa Chaves, Ana Maria Raymundi, Ana Paula Farias Waltrick, José Alexandre de Souza Crippa, Cristina Aparecida Jark Stern, Joice Maria da Cunha, Janaína Menezes Zanoveli Acta Neuropsychiatrica, 2024 Objectives:In view of the neuroprotective characteristic of cannabidiol (CBD) and its beneficial action on aversive memory in non-diabetic animals, we aimed to investigate in animals with experimentally induced type-1 diabetes mellitus (T1DM) whether CBD treatment would be able to impair the contextual fear memory consolidation, its generalisation and whether the effect would be lasting. We also investigated the CBD effect on anxiety-like responses.Methods:After T1DM induction, animals received single or more prolonged treatment with CBD and were submitted to the contextual fear conditioning test. As expression of activity-regulated cytoskeletal-associated (Arc) protein is necessary for memory consolidation, we evaluated its expression in the dorsal hippocampus (DH). For evaluating anxiety-related responses, animals were submitted to the elevated plus maze test (EPMT), in which the time and number of entries in the open arms were used as anxiety index.Results:A single injection of CBD impaired the contextual fear memory consolidation and its generalisation, which was evaluated by exposing the animal in a neutral context. This single injection was able to reduce the elevated expression of Arc in the DH from these animals. Interestingly, more prolonged treatment with CBD also impaired the persistence of context-conditioned fear memory and induced an anxiolytic-like effect, as the treated group spent more time in the open arms of the EPMT.Conclusion:CBD interferes with contextual fear memory and the dosage regimen of treatment seems to be important. Moreover, we cannot rule out the involvement of emotional aspects in these processes related to fear memory.
Pharmacological Interaction Between Cannabidiol and Tramadol on Experimental Diabetic Neuropathic Pain: An Isobolographic Analysis Allan Arnold Evans, Carlos Henrique Alves Jesus, Lucas Latchuk Martins, Alisson Hideki Fukuyama, Alexia Thamara Gasparin, José Alexandre Crippa, Antonio Waldo Zuardi, Jaime Eduardo Cecílio Hallak, Karina Genaro, Célio José de Castro Junior, Janaina Menezes Zanoveli, Joice Maria da Cunha Cannabis and Cannabinoid Research, 2024 Introduction: Diabetic neuropathies are the most prevalent chronic complications of diabetes, characterized by pain and substantial morbidity. Although many drugs have been approved for the treatment of this type of pain, including gabapentin, tramadol (TMD), and classical opioids, it is common to report short-term results or potentially severe side effects. TMD, recommended as a second-line treatment can lead to unwanted side effects. Cannabidiol (CBD) has been gaining attention recently due to its therapeutic properties, including pain management. This study aimed to characterize the pharmacological interaction between CBD and TMD over the mechanical allodynia associated with experimental diabetes using isobolographic analysis. Materials and Methods: After diabetes induction by streptozotocin (STZ), diabetic rats were systemically treated with CBD or TMD alone or in combination (doses calculated based on linear regression of effective dose 40% [ED 40 ]) and had the mechanical threshold evaluated using the electronic Von Frey apparatus. Both experimental and theoretical additive ED 40 values ( Z mix and Z add , respectively) were determined for the combination of CBD plus TMD in this model. Results: Acute treatment with CBD (3 or 10 mg/kg) or TMD (2.5, 5, 10, or 20 mg/kg) alone or in combination (0.38+1.65 or 1.14+4.95 mg/kg) significantly improved the mechanical allodynia in STZ-diabetic rats. Isobolographic analysis revealed that experimental ED 40 of the combination ( Z mix ) was 1.9 mg/kg (95% confidence interval [CI]=1.2–2.9) and did not differ from the theoretical additive ED 40 2.0 mg/kg (95% CI=1.5–2.8; Z add ), suggesting an additive antinociceptive effect in this model. Conclusions: Using an isobolographic analysis, these results provide evidence of additive pharmacological interaction between CBD and TMD over the neuropathic pain associated with experimental diabetes induced by STZ.
A Non-Toxic Binuclear Vanadium(IV) Complex as Insulin Adjuvant Improves the Glycemic Control in Streptozotocin-Induced Diabetic Rats Mateus S. Lopes, Gabriel B. Baptistella, Giovana G. Nunes, Matheus V. Ferreira, Joice Maria Cunha, Kauê Marcel de Oliveira, Alexandra Acco, Maria Luiza C. Lopes, Alexessander Couto Alves, Glaucio Valdameri, Vivian R. Moure, Geraldo Picheth, Graciele C. M. Manica, Fabiane G. M. Rego Pharmaceuticals, 2024 Diabetes mellitus (DM) complications are a burden to health care systems due to the associated consequences of poor glycemic control and the side effects of insulin therapy. Recently. adjuvant therapies, such as vanadium compounds, have gained attention due to their potential to improve glucose homeostasis in patients with diabetes. In order to determine the anti-diabetic and antioxidant effects of the oxidovanadium(IV) complex (Et3NH)2[{VO(OH}2)(ox)2(µ–ox)] or Vox2), rats with streptozotocin (STZ)-induced diabetes were treated with 30 and 100 mg/kg of Vox2, orally administered for 12 days. Vox2 at 100 mg/kg in association with insulin caused a 3.4 times decrease in blood glucose in STZ rats (424 mg/dL), reaching concentrations similar to those in the normoglycemic animals (126 mg/dL). Compared to insulin alone, the association with Vox2 caused an additional decrease in blood glucose of 39% and 65% at 30 and 100 mg/kg, respectively, and an increased pancreatic GSH levels 2.5 times. Vox2 alone did not cause gastrointestinal discomfort, diarrhea, and hepatic or renal toxicity and was not associated with changes in blood glucose level, lipid profile, or kidney or liver function. Our results highlight the potential of Vox2 in association with insulin in treating diabetes.
Spinal cannabinoid CB1 or CB2 receptors activation attenuates mechanical allodynia in streptozotocin-induced diabetic rats Maryna Rodrigues Gonçalves, Milena Santana da Conceição, Carlos Henrique Alves Jesus, Aléxia Thamara Gasparin, Evelize Stacoviaki Rosa, Joice Maria da Cunha Behavioural Pharmacology, 2022 Diabetes is a chronic disease associated with a high number of complications such as peripheral neuropathy, which causes sensorial disturbances and may lead to the development of diabetic neuropathic pain (DNP). The current treatment for DNP is just palliative and the drugs may cause severe adverse effects, leading to discontinuation of treatment. Thus, new therapeutic targets need to be urgently investigated. Studies have shown that cannabinoids have promising effects in the treatment of several pathological conditions, including chronic pain. Thus, we aimed to investigate the acute effect of the intrathecal injection of CB1 or CB2 cannabinoid receptor agonists N-(2-chloroethyl)-5Z, 8Z, 11Z, 14Z-eicosatetraenamide (ACEA) or JWH 133, respectively (10, 30 or 100 μg/rat) on the mechanical allodynia associated with experimental diabetes induced by streptozotocin (60 mg/kg; intraperitoneal) in rats. Cannabinoid receptor antagonists CB1 AM251 or CB2 AM630 (1 mg/kg) were given before treatment with respective agonists to confirm the involvement of cannabinoid CB1 or CB2 receptors. Rats with diabetes exhibited a significant reduction on the paw mechanical threshold 2 weeks after diabetes induction, having the maximum effect observed 4 weeks after the streptozotocin injection. This mechanical allodynia was significantly improved by intrathecal treatment with ACEA or JWH 133 (only at the higher dose of 100 μg). Pre-treatment with AM251 or AM630 significantly reverted the anti-allodynic effect of the ACEA or JWH 133, respectively. Considering the clinical challenge that the treatment of DPN represents, this study showed for the first time, that the intrathecal cannabinoid receptors agonists may represent an alternative for the treatment of DNP.
