Björklund A, Barker RA (2024) The basal forebrain cholinergic system as target for cell replacement therapy in Parkinson’s disease. Brain awae026. doi: 10.1093/brain/awae026 PMID: 38279949

Objective: Review the use of cholinergic cell replacement as a potential therapeutic strategy in Parkinson’s Disease (PD) and how rodent models of PD-like cognitive decline can be used by analyzing rodent and primate studies.

Summary: Although therapies targeting the cholinergic system have so far been focused mainly on patients with Alzheimer´s disease, PD with dementia may be a more relevant condition. In PD with dementia the Basal Forebrain system undergoes progressive degeneration, and the magnitude of cholinergic cell loss has been shown to correlate with the level of cognitive impairment. Thus, cell therapy aimed to replace the lost basal forebrain cholinergic neurons represents an interesting strategy to combat some of the major cognitive impairments in patients with PD dementia.

Usage: Rats were given 192-IgG-SAP (IT-01), 0.2-0.4 μg, delivered as a single 0.3-1.0 μl injection into either the substantia innominate/nucleus basalis of Meynert (SI/NBM) or the medial septum/ventral diagonal band (MS/VDB).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Gao Q, Zhang Y, Wang X, Wang R, Zhang L (2024) Regulation of nociception threshold by norepinephrine through adrenergic α2 receptor in rat models of Parkinson’s disease. CNS Neurosci Ther 30(3):e14446. doi: 10.1111/cns.14446 PMID: 37721421

Objective: To investigate the effect of norepinephrine on the activation of brain cells through adrenergic α2 receptor, to regulate the nociception threshold in a 6-OHDA-induced animal model of Parkinson’s disease (PD).

Summary: The change of norepinephrine content can affect the activation of prefrontal and cingulate gyrus glial cells and participate in the regulation of nociception threshold in PD rats. Adrenergic α2 receptor agonist and central presynaptic membrane α2 receptor blocker both affect cell activation and improve hyperalgesia.

Usage: 4 μL of Anti-DBH-saporin was injected into the right lateral ventricle (1.25 μg/μL, 0.9% NaCl dilution), and injected at the rate of 1 μL/min.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Alhassan M (2022) Sensory and motor visual functions in Parkinson’s Disease with respect to freezing of gait symptoms. J Ophthalmol & Vis Sci 7(2):1069.

Objective: This review article summarizes the results from previous studies focusing on visual functions in Parkinson’s Disease patients.

Summary: Freezing of gait (FOG) is considered to be a motor disorder symptom that affects some Parkinson Disease (PD) patients; however, it is hypothesized that sensory systems may also be involved in FOG. Visual functions include high contrast visual acuity, low contrast visual acuity, contrast sensitivity, Vernier acuity, mesopic vision, stereopsis, motion perception, and vergence eye movements and are all affected in PD patients with FOG patients having more deficits in some of these functions. FOG patients also had impairments in non-dopaminergic mediated functions which suggests greater impairment in two functions that involve cholinergic neurotransmitters. 192-IgG-SAP (Cat. IT-01) was used to create a PD rat animal model to study the contribution of the cholinergic system to motor functions. It was found that the fall rates were more frequent in rats, that were injected with dual 192 IgG-saporin /6-hydroxydopamine (6-OHDA) than rats with either isolated cholinergic or isolated dopaminergic lesions.

Related Products: 192-IgG-SAP (Cat. #IT-01)

See Also:

• Kucinski A et al. Modeling fall propensity in Parkinson’s disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation. J Neurosci 33(42):16522-16539, 2013.

Ujvári B, Pytel B, Márton Z, Bognár M, Kovács LÁ, Farkas J, Gaszner T, Berta G, Kecskés A, Kormos V, Farkas B, Füredi N, Gaszner B (2022) Neurodegeneration in the centrally-projecting Edinger-Westphal nucleus contributes to the non-motor symptoms of Parkinson’s disease in the rat. J Neuroinflammation 19(1):31. doi: 10.1186/s12974-022-02399-w

Objective: To investigate whether neuron loss and alpha-synuclein accumulation in the urocortin 1 containing (UCN1) cells of the centrally-projecting Edinger-Westphal (EWcp) nucleus is associated with anxiety and depression-like state in the rat.

Summary: Neurodegeneration of urocortinergic EWcp contributes to the mood-related non-motor symptoms in toxic models of Parkinson’s disease in the rat.

Usage: Leptin-SAP or unconjugated Saporin (0.08 μl) was injected into the EWcp area. This selective ablation of UCN1 neurons was used to validate the depression-like phenotype in rats. Behavioral, functional–morphological, biochemical and histopathological tools were used to test the motor coordination, mood status as well as morphological changes in the brain.

Related Products: Saporin (Cat. #PR-01), Leptin-SAP (Cat. #IT-47)

Kucinski A, Sarter M (2021) Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071. Psychopharmacology (Berl) 238(7):1953-1964. doi: 10.1007/s00213-021-05822-x

Summary: In addition to the disease-defining motor symptoms, patients with Parkinson’s disease (PD) exhibit gait dysfunction, postural instability, and a propensity for falls. The muscarinic M1-positive allosteric modulator (PAM) TAK-071 improves the attentional performance of rats with BF cholinergic losses. The authors previously developed a rodent model of PD falls by demonstrating that rats with dual basal forebrain cholinergic and mediodorsal striatal dopamine losses (“DL rats”) exhibit a heightened fall rate when required to traverse dynamic surfaces. This study tested the hypothesis that TAK-071 reduces fall rates in DL rats.

Usage: Rats received bilateral infusions of 192-IgG-SAP (200 ng/μL; 0.8 μL/hemisphere) or an equal volume of artificial cerebral spinal fluid into the nucleus basalis and substantia innominata of the basal forebrain.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Pethe P, Kale V (2021) Placenta: A gold mine for translational research and regenerative medicine. Reprod Biol 21(2):100508. doi: 10.1016/j.repbio.2021.100508

Objective: To review recent studies regarding the therapeutic potential of human placenta-derived mesenchymal stromal/stem cells (hPMSCs) and their extracellular vesicles (EVs).

Summary: These studies demonstrate salutary effects of hPMSC-EVs on a range of different difficult-to-treat conditions like Duchenne Muscular Dystrophy, Parkinson’s disease, acute kidney injury, etc., and therefore, it is imperative that these leads should be taken forward to clinical trials.

Usage: 8 µL of 192 IgG-saporin (0.63 µg/µL) were bilaterally injected into the ventricle to induce a dementia rat model.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Bolshakov AP, Stepanichev MY, Dobryakova YV, Spivak, YS, Markevich, VA (2020) Saporin from Saponaria officinalis as a tool for experimental research, modeling, and therapy in neuroscience. Toxins (Basel) 12(9):546. doi: 10.3390/toxins12090546

Summary: A review of studies where saporin-based conjugates were used to analyze cell mechanisms of sleep, general anesthesia, epilepsy, pain, and development of Parkinson’s and Alzheimer’s diseases.

Related Products: Targeted Toxins

Landrigan J, Dwyer Z, Beauchamp S, Rodriguez R, Fortin T, Hayley S (2020) Quantum dot conjugated saporin activates microglia and induces selective substantia nigra degeneration. NeuroToxicology 76:153-161. doi: 10.1016/j.neuro.2019.11.007 PMID: 31738977

Objective: To assess the impact of Quantum Dots (QDs) alone and QDs conjugated to Saporin, on substantia nigra microglia and dopamine neurons.

Summary: QDs might be a viable route for toxicant delivery and also have an added advantage of being fluorescently visible. Ultimately, we found SNc neurons to be exceptionally vulnerable to QD-saporin and suggest that this could be a novel targeted approach to model Parkinson’s Disease-like inflammatory pathology.

Usage: Biotin-labeled saporin chicken polyclonal was mixed with QDs coated with streptavidin. 2  μl of QDs (1 μM) were mixed with 2  μL of biotinylated saporin (56 μM) and 76  μL of phosphate buffer solution was added.

Related Products: Saporin Chicken Polyclonal, affinity-purified biotin-labeled (Cat. #AB-17APBT)

Nazmuddin M, Rao HA, Van Laar T, Sarter MF (2019) How to stimulate: Basal forebrain DBS parameters to restore the attentional performance of rats with cholinergic losses. Neuroscience 2019 Abstracts 377.10. Society for Neuroscience, Chicago, IL.

Summary: The degeneration of basal forebrain (BF) cholinergic neurons is an index of the severity of cognitive impairment in Alzheimer disease (AD) and Parkinson’s disease (PD). Moreover, in PD patients, gait and balancing deficits, and an increased propensity for falls have been attributed to cholinergic losses. Thus, Deep Brain Stimulation (DBS) of the BF has been considered a potential therapeutic intervention to improve cognition and movement control in these patients. However, efficacy of BF DBS in clinical populations has yet to be conclusively demonstrated. Likewise, the demonstration of beneficial effects of BF DBS in rodent models has been hampered by uncertainties about useful animal models and behavioral tasks and, importantly, a lack of consensus concerning DBS parameters (duration, frequency, current, intermittent versus continuous, prior and/or during task, etc.). Here we assessed various DBS parameters in rats with a partial loss of the cortical cholinergic input system. In rats, such cholinergic losses have been frequently demonstrated to impair the detection of cues during the performance of a Sustained Attention Task (SAT) and to attenuate performance recovery following a distractor challenge (dSAT). In PD patients with cholinergic losses, attentional impairments were also attributed to cortical and thalamic cholinergic losses (Kim et al., 2017). The attribution of SAT impairments to cholinergic losses is consistent with evidence showing that the detection of cues and associated attentional control parameters depend on cortical cholinergic signaling (e.g., Howe et al., 2017). Here, rats acquired the SAT, received infusions of the cholino-specific neurotoxin 192-IgG-saporin into the BF, and were implanted bilaterally with BF unipolar stimulation electrodes. Initial DBS parameters consisted of continuous high (130 Hz) versus low (20 Hz) frequency stimulation, intermittent (20-s ON at 80 Hz and 40-s OFF) stimulation, with pulse width and amplitude kept constant at 100 µs and 100 µA, respectively. We first assessed the effects of these DBS parameters on the behavior of rats in an open field space and then when administered during, or only prior to (for 1 hr), SAT and dSAT performance. Ongoing experiments indicate that these stimulation parameters are well tolerated as indicated by the absence of effects on locomotor and exploratory activity. We predict that BF DBS will be particularly effective in restoring attentional performance in the dSAT condition. If confirmed, this finding will suggest that demonstration of efficacy in patients will require measures indicating their attentional capacities in response to taxing performance challenges.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Koshy Cherian A, Kucinski A, Wu R, deJong IEM, Sarter M (2019) Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson’s disease. Psychopharmacology 236:1701–1715. doi: 10.1007/s00213-018-5150-y

Objective: The authors used a longer and more taxing rotating beam apparatus to determine the potential therapeutic efficacy of idalopirdine when combined with rivastigmine.

Summary: The results extend the prediction that the combined treatment with idalopirdine and an AChE inhibitor improves complex movement control and reduces propensity for falls in patients with movement disorders.

Usage: Basal forebrain cholinergic neurons situated in the nucleus basalis and substantia innominata were targeted with 192-IgG-SAP in aCSF infused bilaterally (200 ng/μL; 0.8 μL/hemisphere).

Related Products: 192-IgG-SAP (Cat. #IT-01)