Felipe Patricio Martinez | Benemérita Universidad Autónoma de Puebla (BUAP) (original) (raw)
Papers by Felipe Patricio Martinez
Frontiers in Pharmacology, 2022
Cannabidiol (CBD), the major non-psychoactive phytocannabinoid present in the plant Cannabis sati... more Cannabidiol (CBD), the major non-psychoactive phytocannabinoid present in the plant Cannabis sativa, has displayed beneficial pharmacological effects in the treatment of several neurological disorders including, epilepsy, Parkinson's disease, and Alzheimer's disease. In particular, CBD is able to modulate different receptors in the endocannabinoid system, some of which belong to the family of G-protein-coupled receptors (GPCRs). Notably, while CBD is able to antagonize some GPCRs in the endocannabinoid system, it also seems to activate others. The details of this dual contrasting functional feature of CBD, that is, displaying antagonistic and (possible) agonistic ligand properties in related receptors, remain unknown. Here, using computational methods, we investigate the interacting determinants of CBD in two closely related endocannabinoid-activated GPCRs, the G-protein-coupled receptor 55 (GPR55) and the cannabinoid type 1 receptor (CB 1). While in the former, CBD has been demonstrated to function as an antagonist, the way by which CBD modulates the CB 1 receptor remains unclear. Namely, CBD has been suggested to directly trigger receptor's activation, stabilize CB 1 inactive conformations or function as an allosteric modulator. From microsecondlength unbiased molecular dynamics simulations, we found that the presence of the CBD ligand in the GPR55 receptor elicit conformational changes associated with antagonist-bound GPCRs. In contrast, when the GPR55 receptor is simulated in complex with the selective agonist ML186, agonist-like conformations are sampled. These results are in agreement with the proposed modulatory function of each ligand, showing that the computational techniques utilized to characterize the GPR55 complexes correctly differentiate the agonist-bound and antagonist-bound systems. Prompted by these results, we investigated the role of the CBD compound
Frontiers in Neuroscience, 2022
Evidence suggests that SARS-CoV-2 entry into the central nervous system can result in neurologica... more Evidence suggests that SARS-CoV-2 entry into the central nervous system can result in neurological and/or neurodegenerative diseases. In this review, routes of SARS-Cov-2 entry into the brain via neuroinvasive pathways such as transcribrial, ocular surface or hematogenous system are discussed. It is argued that SARS-Cov-2-induced cytokine storm, neuroinflammation and oxidative stress increase the risk of developing neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Further studies on the effects of SARS-CoV-2 and its variants on protein aggregation, glia or microglia activation, and blood-brain barrier are warranted.
Multimedia Tools and Applications, 2022
Animal models are helpful to evaluate the effects of some drugs in the treatment of brain disease... more Animal models are helpful to evaluate the effects of some drugs in the treatment of brain diseases, such as the case of the Open Field Maze. Usually, these tests are recorded in video and analysed afterwards to carry out manual annotations about the activity and behaviour of the rat. Usually, these videos must be watched repeatedly to ensure correct annotations, but they are prone to become a tedious task and are highly likely to produce human errors. Existing commercial systems for automatic detection of the rat and classification of its behaviours may become inaccessible for research teams that cannot afford the license cost. Motivated by the latter, we propose a methodology for simultaneous rat detection and behaviour classification using inexpensive hardware in this work. Our proposal is a Deep Learning-based two-step methodology to simultaneously detect the rat in the test and classify its behaviour. In the first step, a single shot detector network is used to detect the rat; then, the systems crop the image using the bounding box to generate a sequence of six images that input our BehavioursNet network to classify the rodent's behaviour. Finally, based on the results of these steps, the system generates an ethogram for the complete video, a trajectory plot, a heatmap plot for most visited regions and a video showing the rat's detection and its behaviours. Our results show that it is possible to perform these tasks at a processing rate of 23 Hz, with a low error of 6 pixels in the detection and a first approach to classify ambiguous behaviours such as resting and grooming, with an average precision of 60%, which is competitive with that reported in the literature.
Neuroscience Research, 2021
The recombinant carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) exerts neu... more The recombinant carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) exerts neuroprotective and neurorestorative effects on the dopaminergic system of animal models of Parkinson's disease (PD). The present study aimed to determine the effect of the Hc-TeTx fragment on the markers of oxidative stress and nitrosative stress generated by the acute toxicity of 1-methyl-4-phenylpyridinium (MPP+). For this purpose, the Hc-TeTx fragment was administered once a day in three 20 μg/kg consecutive injections into the grastrocnemius muscle of the rats, with an intra-striatal unilateral injection of 1 μL of MPP+ [10 μg/mL] then administered in order to cause a dopaminergic lesion. The results obtained show that the rats treated with Hc-TeTx plus MPP+ presented an increase in the expression of tyrosine hydroxylase (TH), a significantly greater decrease in the levels of the markers of oxidative stress, nitrosative stress, and neurodegeneration than that observed for the group injured with only MPP+. Moreover, it was observed that total superoxide dismutase (SOD) and copper/zinc SOD activity increased with the administration of Hc-TeTx. Finally, immunoreactivity levels were observed to decrease for the levels of 3-nitrotyrosine and the glial fibrillary acidic protein in the ipsilateral striatum of the rats treated with Hc-TeTx plus MPP+, in contrast with those lesioned with MPP+ alone. Our results demonstrate that the recombinant Hc-TeTx fragment may be a potent antioxidant and, therefore, could be suggested as a therapeutic tool against the dopaminergic neuronal impairment observed in the early stages of PD.
Frontiers in Pharmacology, 2020
The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmac... more The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmacological alternative for treating various central nervous system (CNS) disorders. Interestingly, cannabinoid receptors (CBRs) are highly expressed in the basal ganglia (BG) circuit of both animals and humans. The BG are subcortical structures that regulate the initiation, execution, and orientation of movement. CBRs regulate dopaminergic transmission in the nigro-striatal pathway and, thus, the BG circuit also. The functioning of the BG is affected in pathologies related to movement disorders, especially those occurring in Parkinson's disease (PD), which produces motor and non-motor symptoms that involving GABAergic, glutamatergic, and dopaminergic neural networks. To date, the most effective medication for PD is levodopa (L-DOPA); however, long-term levodopa treatment causes a type of long-term dyskinesias, L-DOPA-induced dyskinesias (LIDs). With neuromodulation offering a novel treatment strategy for PD patients, research has focused on the endocannabinoid system (ECS), as it participates in the physiological neuromodulation of the BG in order to control movement. CBRs have been shown to inhibit neurotransmitter release, while endocannabinoids (eCBs) play a key role in the synaptic regulation of the BG. In the past decade, cannabidiol (CBD), a non-psychotropic phytocannabinoid, has been shown to have compensatory effects both on the ECS and as a neuromodulator and neuroprotector in models such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and reserpine, as well as other PD models. Although the CBD-induced neuroprotection observed in animal models of PD has been attributed to the activation of the CB1 receptor, recent research conducted at a molecular level has proposed that CBD is capable of activating other receptors, such as CB2 and the TRPV-1
Reports indicate that striatal dopaminergic damage induced by 6-hydoxydopamine (6-OHDA) can be bl... more Reports indicate that striatal dopaminergic damage induced by 6-hydoxydopamine (6-OHDA) can be blocked by C-terminal domain of tetanus toxin (Hc-TeTx), suggesting possible therapeutic potential of Hc-TeTx in Parkinson’s disease (PD). Pramipexole (PPX), a D2/D3 dopaminergic agonist, is currently used in PD treatment. The purpose of this study was to gain some understanding of the actions of each drug, including potential antioxidant and anti-inflammatory effects and importantly, to determine whether the combination of the two drugs would be superior to each alone. Adult male Wistar rats were administered 6-OHDA into the dorsolateral striatum, and the effects of Hc-TeTx fragment (20 μg/kg i.m. every 24 h) for 3 days; PPX (1 mg/kg p.o., every 12 h) for 30 days and their combination on various motor and neurochemical parameters were evaluated. Behavioral tests were carried out at 15 and 30 days post-treatments. At day 31, the animals were sacrificed and the levels of tyrosine hydroxylase (TH), reflecting dopaminergic activity in both striatum and substantia nigra, were evaluated. In addition, indices of astrogliosis, microgliosis, as well as oxidative stress in the striatum were determined. Both Hc-TeTx and PPX ameliorated the motor and neurochemical deficits induced by 6-OHDA lesion; however, the combination of the two drugs was not superior to each alone. Hence, at concentrations used in this study, no significant advantage in combining Hc-TeTx with PPX was noted. Although the results suggest similar neurochemical effects of the two compounds, further evaluation of different concentrations of Hc-TeTx and PPX as potential intervention in PD is warranted.
Experimental and clinical cardiology
Elevated levels of aldosterone are associated with deleterious effects on the cardiovascular syst... more Elevated levels of aldosterone are associated with deleterious effects on the cardiovascular system, which contributes to the development of endothelial dysfunction, fibrosis and inflammation hypertrophy, heart failure, sympathetic activation, stroke and renal dysfunction. Furthermore, it has been shown that treatment with mineralocorticoid receptor antagonists reduce the progressive damage that occurs in aldosterone target organs of patients with hypertension or heart failure, both in humans and in dogs; however, the expression of such receptors has only been demonstrated in human cardiac tissues, rabbit and rat, not so in the dog. To determine the expression of aldosterone receptors in cardiac tissues of healthy dogs, we employ the technique of immunohistochemistry for positive labeling with specific antibody in the hearts of two clinically healthy beagle dogs. Immunohistochemical assays performed, showed for first time, unpublished results of positive immunoreactivity to aldoster...
Frontiers in Pharmacology, 2022
Cannabidiol (CBD), the major non-psychoactive phytocannabinoid present in the plant Cannabis sati... more Cannabidiol (CBD), the major non-psychoactive phytocannabinoid present in the plant Cannabis sativa, has displayed beneficial pharmacological effects in the treatment of several neurological disorders including, epilepsy, Parkinson's disease, and Alzheimer's disease. In particular, CBD is able to modulate different receptors in the endocannabinoid system, some of which belong to the family of G-protein-coupled receptors (GPCRs). Notably, while CBD is able to antagonize some GPCRs in the endocannabinoid system, it also seems to activate others. The details of this dual contrasting functional feature of CBD, that is, displaying antagonistic and (possible) agonistic ligand properties in related receptors, remain unknown. Here, using computational methods, we investigate the interacting determinants of CBD in two closely related endocannabinoid-activated GPCRs, the G-protein-coupled receptor 55 (GPR55) and the cannabinoid type 1 receptor (CB 1). While in the former, CBD has been demonstrated to function as an antagonist, the way by which CBD modulates the CB 1 receptor remains unclear. Namely, CBD has been suggested to directly trigger receptor's activation, stabilize CB 1 inactive conformations or function as an allosteric modulator. From microsecondlength unbiased molecular dynamics simulations, we found that the presence of the CBD ligand in the GPR55 receptor elicit conformational changes associated with antagonist-bound GPCRs. In contrast, when the GPR55 receptor is simulated in complex with the selective agonist ML186, agonist-like conformations are sampled. These results are in agreement with the proposed modulatory function of each ligand, showing that the computational techniques utilized to characterize the GPR55 complexes correctly differentiate the agonist-bound and antagonist-bound systems. Prompted by these results, we investigated the role of the CBD compound
Frontiers in Neuroscience, 2022
Evidence suggests that SARS-CoV-2 entry into the central nervous system can result in neurologica... more Evidence suggests that SARS-CoV-2 entry into the central nervous system can result in neurological and/or neurodegenerative diseases. In this review, routes of SARS-Cov-2 entry into the brain via neuroinvasive pathways such as transcribrial, ocular surface or hematogenous system are discussed. It is argued that SARS-Cov-2-induced cytokine storm, neuroinflammation and oxidative stress increase the risk of developing neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Further studies on the effects of SARS-CoV-2 and its variants on protein aggregation, glia or microglia activation, and blood-brain barrier are warranted.
Multimedia Tools and Applications, 2022
Animal models are helpful to evaluate the effects of some drugs in the treatment of brain disease... more Animal models are helpful to evaluate the effects of some drugs in the treatment of brain diseases, such as the case of the Open Field Maze. Usually, these tests are recorded in video and analysed afterwards to carry out manual annotations about the activity and behaviour of the rat. Usually, these videos must be watched repeatedly to ensure correct annotations, but they are prone to become a tedious task and are highly likely to produce human errors. Existing commercial systems for automatic detection of the rat and classification of its behaviours may become inaccessible for research teams that cannot afford the license cost. Motivated by the latter, we propose a methodology for simultaneous rat detection and behaviour classification using inexpensive hardware in this work. Our proposal is a Deep Learning-based two-step methodology to simultaneously detect the rat in the test and classify its behaviour. In the first step, a single shot detector network is used to detect the rat; then, the systems crop the image using the bounding box to generate a sequence of six images that input our BehavioursNet network to classify the rodent's behaviour. Finally, based on the results of these steps, the system generates an ethogram for the complete video, a trajectory plot, a heatmap plot for most visited regions and a video showing the rat's detection and its behaviours. Our results show that it is possible to perform these tasks at a processing rate of 23 Hz, with a low error of 6 pixels in the detection and a first approach to classify ambiguous behaviours such as resting and grooming, with an average precision of 60%, which is competitive with that reported in the literature.
Neuroscience Research, 2021
The recombinant carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) exerts neu... more The recombinant carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) exerts neuroprotective and neurorestorative effects on the dopaminergic system of animal models of Parkinson's disease (PD). The present study aimed to determine the effect of the Hc-TeTx fragment on the markers of oxidative stress and nitrosative stress generated by the acute toxicity of 1-methyl-4-phenylpyridinium (MPP+). For this purpose, the Hc-TeTx fragment was administered once a day in three 20 μg/kg consecutive injections into the grastrocnemius muscle of the rats, with an intra-striatal unilateral injection of 1 μL of MPP+ [10 μg/mL] then administered in order to cause a dopaminergic lesion. The results obtained show that the rats treated with Hc-TeTx plus MPP+ presented an increase in the expression of tyrosine hydroxylase (TH), a significantly greater decrease in the levels of the markers of oxidative stress, nitrosative stress, and neurodegeneration than that observed for the group injured with only MPP+. Moreover, it was observed that total superoxide dismutase (SOD) and copper/zinc SOD activity increased with the administration of Hc-TeTx. Finally, immunoreactivity levels were observed to decrease for the levels of 3-nitrotyrosine and the glial fibrillary acidic protein in the ipsilateral striatum of the rats treated with Hc-TeTx plus MPP+, in contrast with those lesioned with MPP+ alone. Our results demonstrate that the recombinant Hc-TeTx fragment may be a potent antioxidant and, therefore, could be suggested as a therapeutic tool against the dopaminergic neuronal impairment observed in the early stages of PD.
Frontiers in Pharmacology, 2020
The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmac... more The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmacological alternative for treating various central nervous system (CNS) disorders. Interestingly, cannabinoid receptors (CBRs) are highly expressed in the basal ganglia (BG) circuit of both animals and humans. The BG are subcortical structures that regulate the initiation, execution, and orientation of movement. CBRs regulate dopaminergic transmission in the nigro-striatal pathway and, thus, the BG circuit also. The functioning of the BG is affected in pathologies related to movement disorders, especially those occurring in Parkinson's disease (PD), which produces motor and non-motor symptoms that involving GABAergic, glutamatergic, and dopaminergic neural networks. To date, the most effective medication for PD is levodopa (L-DOPA); however, long-term levodopa treatment causes a type of long-term dyskinesias, L-DOPA-induced dyskinesias (LIDs). With neuromodulation offering a novel treatment strategy for PD patients, research has focused on the endocannabinoid system (ECS), as it participates in the physiological neuromodulation of the BG in order to control movement. CBRs have been shown to inhibit neurotransmitter release, while endocannabinoids (eCBs) play a key role in the synaptic regulation of the BG. In the past decade, cannabidiol (CBD), a non-psychotropic phytocannabinoid, has been shown to have compensatory effects both on the ECS and as a neuromodulator and neuroprotector in models such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and reserpine, as well as other PD models. Although the CBD-induced neuroprotection observed in animal models of PD has been attributed to the activation of the CB1 receptor, recent research conducted at a molecular level has proposed that CBD is capable of activating other receptors, such as CB2 and the TRPV-1
Reports indicate that striatal dopaminergic damage induced by 6-hydoxydopamine (6-OHDA) can be bl... more Reports indicate that striatal dopaminergic damage induced by 6-hydoxydopamine (6-OHDA) can be blocked by C-terminal domain of tetanus toxin (Hc-TeTx), suggesting possible therapeutic potential of Hc-TeTx in Parkinson’s disease (PD). Pramipexole (PPX), a D2/D3 dopaminergic agonist, is currently used in PD treatment. The purpose of this study was to gain some understanding of the actions of each drug, including potential antioxidant and anti-inflammatory effects and importantly, to determine whether the combination of the two drugs would be superior to each alone. Adult male Wistar rats were administered 6-OHDA into the dorsolateral striatum, and the effects of Hc-TeTx fragment (20 μg/kg i.m. every 24 h) for 3 days; PPX (1 mg/kg p.o., every 12 h) for 30 days and their combination on various motor and neurochemical parameters were evaluated. Behavioral tests were carried out at 15 and 30 days post-treatments. At day 31, the animals were sacrificed and the levels of tyrosine hydroxylase (TH), reflecting dopaminergic activity in both striatum and substantia nigra, were evaluated. In addition, indices of astrogliosis, microgliosis, as well as oxidative stress in the striatum were determined. Both Hc-TeTx and PPX ameliorated the motor and neurochemical deficits induced by 6-OHDA lesion; however, the combination of the two drugs was not superior to each alone. Hence, at concentrations used in this study, no significant advantage in combining Hc-TeTx with PPX was noted. Although the results suggest similar neurochemical effects of the two compounds, further evaluation of different concentrations of Hc-TeTx and PPX as potential intervention in PD is warranted.
Experimental and clinical cardiology
Elevated levels of aldosterone are associated with deleterious effects on the cardiovascular syst... more Elevated levels of aldosterone are associated with deleterious effects on the cardiovascular system, which contributes to the development of endothelial dysfunction, fibrosis and inflammation hypertrophy, heart failure, sympathetic activation, stroke and renal dysfunction. Furthermore, it has been shown that treatment with mineralocorticoid receptor antagonists reduce the progressive damage that occurs in aldosterone target organs of patients with hypertension or heart failure, both in humans and in dogs; however, the expression of such receptors has only been demonstrated in human cardiac tissues, rabbit and rat, not so in the dog. To determine the expression of aldosterone receptors in cardiac tissues of healthy dogs, we employ the technique of immunohistochemistry for positive labeling with specific antibody in the hearts of two clinically healthy beagle dogs. Immunohistochemical assays performed, showed for first time, unpublished results of positive immunoreactivity to aldoster...